JP2018500304A - Hydroxy-containing FXR (NR1H4) modulating compound - Google Patents

Abstract

The present invention relates to a compound (1) that binds to the NR1H4 receptor (FXR) and acts as an agonist of FXR. The present invention relates to the use of the present compound (1) for the preparation of a medicament for the treatment of diseases and / or conditions through binding to said nuclear receptor by said compound and for the synthesis of said compound Further to the process. In a further embodiment, the present invention relates to compounds according to formula (1) for use in the prevention and / or treatment of diseases mediated by FXR.

Description

  The present invention relates to compounds that bind to the NR1H4 receptor (FXR) and act as agonists or modulators of FXR. The invention further relates to the use of the compounds for the treatment and / or prevention of diseases and / or conditions through binding to the nuclear receptor by the compounds.

  Multicellular organisms rely on sophisticated mechanisms of communication between cells and body compartments. The information transmitted can be quite complex and can result in alterations in the genetic program involved in cell differentiation, proliferation, or regeneration. The signal, or hormone, is often a low molecular weight molecule such as a peptide, fatty acid, or cholesterol derivative.

  Many of these signals effect these effects by ultimately altering the transcription of specific genes. One well-studied group of proteins that mediate cellular responses to a variety of signals, known as nuclear receptors (hereinafter often referred to as “NR”) Is a family of transcription factors. Members of this group include receptors for steroid hormones, vitamin D, ecdysone, cis and trans retinoic acid, thyroid hormones, bile acids, cholesterol derivatives, fatty acids (and other peroxisome growth factors), and so-called orphan receptors, That is, it includes proteins that are structurally similar to the other members of this group, but whose ligands are not known. Orphan receptors may exhibit unknown signaling pathways in the cell or may be nuclear receptors that function without ligand activation. Transcriptional activation by some of these orphan receptors can occur in the absence of exogenous ligands and / or via signal transduction pathways originating from the cell surface (DJ Mangelsdorf et al., Cell, 1995). 83, 835; RM Evans, Mol. Endocrinol. 2005, 19, 1429).

  In general, three functional domains are defined in NR. The amino terminal domain is believed to have some regulatory function. This is followed by a DNA binding domain (hereinafter referred to as “DBD” hereinafter), which usually contains two zinc finger elements and contains specific hormone response elements (in the promoter of the response gene ( (Hereinafter referred to as “HRE”) in this specification. Specific amino acid residues in “DBD” have been shown to confer DNA sequence binding specificity (M. Schena and K.R. Yamamoto, Science, 1988, 241, 965). The ligand binding domain (hereinafter referred to as “LBD” hereinafter) is in the carboxy-terminal region of the known NR.

  In the absence of hormones, LBD appears to prevent the interaction between DBD and its HRE. Hormone binding results in a structural change in NR and thus appears to lift this blockage (A.M. Brzozowski et al., Nature, 1997, 389, 753). NR without LBD constitutively activates transcription, albeit at a low level.

  Co-activators or transcription activators have been proposed to bridge between sequence-specific transcription factors, basal transcription machinery parts, and in addition, affect the chromatin structure of target cells. Several proteins such as SRC-1, ACTR, and Grip1 interact with NR to enhance ligands (DM Heery et al., Nature, 1997, 387, 733; T. Heinzel et al., Nature 1997, 387, 43; KW Nettles and GL Greene, Annu. Rev. Physiol., 2005, 67, 309).

  Nuclear receptor modulators such as steroid hormones affect specific cell proliferation and function by binding to intracellular receptors and forming nuclear receptor-ligand complexes. The nuclear receptor-hormone complex then interacts with the HRE in the control region of the specific gene to change the expression of the specific gene (A. Aranda and A. Pascual, Physiol. Rev., 2001). Year, 81, 1269).

  Farnesoid X receptor alpha (hereinafter referred to hereinafter as human receptor, often referred to as NR1H4) is a typical type 2 nuclear receptor, Binding to the promoter region of the target gene in the form of a heterodimer with the retinoid X receptor activates the gene (BM Forman et al., Cell, 1995, 81, 687). The relevant physiological ligand of NR1H4 is bile acid (D.J. Parks et al., Science 1999, 284, 1365; M. Makishima et al., Science, 1999, 284, 1362). The most powerful is chenodeoxycholic acid (CDCA), which regulates the expression of several genes involved in bile acid homeostasis. Although farnesol and derivatives (collectively referred to as farnesoids) were originally described to activate rat orthologs at high concentrations, they do not activate human or mouse receptors. FXR is expressed in the ovary, adrenal gland, and kidney throughout the gastrointestinal tract, including the liver, esophagus, stomach, duodenum, small intestine, and colon. In addition to controlling intracellular gene expression, FXR also regulates paracrine and endocrine signaling by upregulating the expression of cytokine fibroblast growth factor 15 (rodent) or 19 (monkey, human). It seems to be involved (JA Holt et al., Genes Dev., 2003, 17, 1581; T. Inagaki et al., Cell Metab., 2005, 2, 217).

  Small molecule compounds that act as FXR modulators are disclosed in the following publications: WO 2000/037077, WO 2003/015771, WO 2004/048349, WO 2007/076260, WO 2007/092751, WO 2007/140174, WO 2007/140183, WO 2008 / 051942, WO2008 / 157270, WO2009 / 005998, WO2009 / 012125, WO2008 / 025539, WO2008 / 0255540, WO2009 / 005998, WO2009 / 0149795, WO2011 / 020615, WO2012 / 087519 and WO2013 / 007387. Additional small molecule FXR modulators have recently been reviewed (ML Crawley, Expert Opin Ther. Pat., 2010, 20, 1047; D. Merk et al., Future Med. Chem. 2012, 4, 1015 and C. Gege et al., Curr. Top. Med. Chem., 2014, 14, 2143).

In WO2009 / 012125, isoxazole derivatives of general structure (A) are described as FXR agonists. The compounds contain a central cyclohexane, cycloheptane, piperidine or azepane ring system (where X is a carbon or nitrogen atom) in which no substitution is disclosed or claimed.

WO 2012/087520 discloses FXR agonists of general formula (B) in which benzo [d] thiazol-2-yl is linked to the central pyrrolidine or piperidine ring nitrogen. Again, the substitution of central pyrrolidine or piperidine is not disclosed.

Similarly, WO2012 / 087521 discloses FXR agonists of general formula (C) in which 1,2,4-oxadiazol-3-yl is linked to the nitrogen of the central piperidine ring. Again, substitution of the central piperidine is not disclosed.

International Publication No. 2000/037077 International Publication No. 2003/015771 International Publication No. 2004/048349 International Publication No. 2007/076260 International Publication No. 2007/092751 International Publication No. 2007/140174 International Publication No. 2007/140183 International Publication No. 2008/051942 International Publication No. 2008/157270 International Publication No. 2009/005998 International Publication No. 2009/012125 International Publication No. 2008/0255539 International Publication No. 2008/025540 International Publication No. 2009/149795 International Publication No. 2011/020615 International Publication No. 2012/087519 International Publication No. 2013/007387 International Publication No. 2012/087520 International Publication No. 2012/087521

D. J. Mangelsdorf et al., Cell, 1995, 83, 835. R. M. Evans, Mol. Endocrinol., 2005, 19, 1429 M. Schena and K.R. Yamamoto, Science, 1988, 241, 965 A.M. Brzozowski et al., Nature, 1997, 389, 753. D.M. Heery et al., Nature, 1997, 387, 733. T. Heinzel et al., Nature, 1997, 387, 43. K.W. Nettles and G.L.Greene, Annu. Rev. Physiol., 2005, 67, 309 A. Aranda and A. Pascual, Physiol. Rev., 2001, 81, 1269 B.M.Forman et al., Cell, 1995, 81, 687. D.J. Parks et al., Science 1999, 284, 1365 M. Makishima et al., Science 1999, 284, 1362 J. A. Holt et al., Genes Dev., 2003, 17, 1581 T. Inagaki et al., Cell Metab., 2005, Vol. 2, 217 M.L.Crawley, Expert Opin Ther. Pat., 2010, 20, 1047 D. Merk et al., Future Med. Chem. 2012, 4, 1015 C. Gege et al., Curr. Top. Med. Chem., 2014, 14, 2143

  However, there is still a need for improved FXR-agonists. Thus, the problem underlying the present invention is a novel FXR-agonist that generally has higher physicochemical properties, particularly lower hydrophobicity, and higher water solubility compared to compounds known in the art. Is the generation of

  Said problem is solved by FXR-agonists according to formula (1), which have higher physicochemical properties compared to known FXR-agonists. In particular, the introduction of a hydroxyl group at the carbon atom of moiety Q linked to moiety A is calculated between the calculated value of a known FXR-agonist having the relevant structure and the calculated clogP and tPSA of Example 4 of the present invention. As can be taken from FIG. 1, which shows the comparison, it leads to a decrease in clogP, an increase in topological polar surface area and thus an improvement in water solubility compared to the related structure disclosed in WO2012 / 087520. At the same time, the compounds of the invention maintain high activity on the FXR-receptor in both biochemical and cellular assays. More specifically, compounds of the present invention having a cis structure of two oxygen substituents in the central cyclic alkyl moiety Q have higher activity on the FXR receptor than those having a trans structure.

［式中、
Ｒは、水素、ハロゲン、Ｃ_１〜６−アルキル、Ｃ_２〜６−アルケニル、Ｃ_２〜６−アルキニル、ハロ−Ｃ_１〜６−アルキル、Ｃ_０〜６−アルキレン−Ｒ^７、Ｃ_０〜６−アルキレン−Ｏ−Ｒ^７、Ｃ_０〜６−アルキレン−ＣＮ、Ｃ_０〜６−アルキレン−ＮＲ^７Ｒ^８、Ｏ−Ｃ_３〜１０−シクロアルキル、Ｏ−Ｃ_１〜６−アルキレン−Ｏ−Ｒ^７、Ｏ−Ｃ_３〜１０−ヘテロシクロアルキル、Ｃ_０〜６−アルキレン−ＣＯ_２Ｒ^７、Ｃ_０〜６−アルキレン−Ｃ（Ｏ）Ｒ^７、Ｃ_０〜６−アルキレン−Ｃ（Ｏ）ＮＲ^７Ｒ^８、Ｃ_０〜６−アルキレン−Ｃ（Ｏ）ＮＲ^７ＳＯ_２Ｒ^７、Ｃ_０〜６−アルキレン−Ｎ（Ｒ^７）Ｃ（Ｏ）Ｒ^７、Ｃ_０〜６−アルキレン−ＳＯ_ｘ−Ｒ^７、Ｃ_０〜６−アルキレン−ＳＯ_３Ｈ、Ｃ_０〜６−アルキレン−ＳＯ_２−ＮＲ^７Ｒ^８、Ｃ_０〜６−アルキレン−ＳＯ_２−ＮＲ^８ＣＯＲ^７、Ｃ_０〜６−アルキレン−Ｎ（Ｒ^７）ＳＯ_２−Ｒ^８、およびＣ_０〜６−アルキレン−ＳＯ_２−Ｃ_３〜１０−ヘテロシクロアルキルからなる群から選択され、
ここで、アルキレン、シクロアルキル、ヘテロシクロアルキルおよび５または６員のヘテロアリールは、非置換であるか、またはハロゲン、ＣＮ、Ｃ_１〜３−アルキル、ハロ−Ｃ_１〜３−アルキル、ＯＨ、オキソ、ＣＯ_２Ｈ、ＳＯ_３Ｈ、Ｏ−Ｃ_１〜３−アルキルおよびＯ−ハロ−Ｃ_１〜３−アルキルからなる群から独立に選択される１から４個の置換基によって置換されており、
Ｒ^７は、水素、Ｃ_１〜６−アルキル、ハロ−Ｃ_１〜６−アルキル、Ｃ_０〜６−アルキレン−Ｃ_３〜８−シクロアルキル、Ｃ_０〜６−アルキレン−Ｃ_３〜８−ヘテロシクロアルキル、５または６員のヘテロアリールおよびフェニルからなる群から独立に選択され、ここで、アルキル、アルキレン、シクロアルキル（cyclolalkyl）、ヘテロシクロアルキル、フェニルおよびヘテロアリールは、非置換であるか、またはハロゲン、ＣＮ、ＯＨ、オキソ、ＣＯ_２Ｈ、Ｃ_１〜３−アルキル、ハロ−Ｃ_１〜３−アルキル、Ｏ−Ｃ_１〜３−アルキル、Ｏ−ハロ−Ｃ_１〜３−アルキル、ＳＯ_３ＨおよびＳＯ_２−Ｃ_１〜３−アルキルからなる群から独立に選択される１から６個の置換基で置換されており、
Ｒ^８は、水素、Ｃ_１〜６−アルキル、ハロ−Ｃ_１〜６−アルキルおよびＣ_３〜６−シクロアルキルからなる群から独立に選択されるか、
あるいは、Ｒ^７およびＲ^８は、それらが結合している窒素と一緒になると、炭素原子を含有し、かつＯ、ＳまたはＮから選択される１または２個のヘテロ原子を任意選択で含有する３から８員の環を完成させてよく、ここで、環は、非置換であるか、またはフルオロ、ＯＨ、オキソ、Ｃ_１〜４−アルキルおよびハロ−Ｃ_１〜４−アルキルからなる群から独立に選択される１から４個の置換基で置換されており、
Ａは、６〜１０員の単環式もしくは二環式アリール、またはＮ、ＯおよびＳからなる群から独立に選択される１から５個のヘテロ原子を含有する５〜１０員の単環式もしくは二環式ヘテロアリールであり、ここで、アリールおよびヘテロアリールは、非置換であるか、またはＯＨ、ハロゲン、ＣＮ、Ｏ−Ｃ_１〜６−アルキル、Ｏ−ハロ−Ｃ_１〜６−アルキル、Ｃ_１〜６−アルキル、ハロ−Ｃ_１〜６−アルキル、Ｃ_３〜６−シクロアルキル、Ｃ_５〜６−ヘテロシクロアルキルおよびハロ−Ｃ_３〜６−シクロアルキルからなる群から独立に選択される１または２個の基で置換されており、
Ｑは、Ｃ_３〜１０−シクロアルキル環、またはＣ_５〜１０−架橋シクロアルキル環であり、−Ｏ−ＣＨ_２−Ｚ−置換基は、置換基Ａに直接隣接しておらず、Ｑが二環式または多環式環系である場合、炭素原子は、酸素、ＳＯ_ｘまたはＮＲ^７で、任意選択で置き換えられていてもよく、
Ｚは、

から選択され
式中、
Ｌは、結合、Ｃ_１〜３−アルキレンおよびＣ_１〜３−アルキレン−Ｏ−からなる群から選択され、
Ｙは、フェニル、ピリジル、ピリジル−Ｎ−オキシド、ピリミジル、ピリジノニル、ピリミジノニル、Ｃ_４〜８−シクロアルキルまたはＣ_４〜８−ヘテロシクロアルキルからなる群から選択され、ここで、フェニル、ピリジル、ピリジル−Ｎ−オキシド、ピリミジル、ピリジノニル、ピリミジノニル、Ｃ_４〜８−シクロアルキルおよびＣ_４〜８−ヘテロシクロアルキルは、Ｒ^２およびＲ^３で置換されており、フルオロ、クロロ、ＣＮ、ＮＨ_２、ＮＨ（Ｃ_１〜３−アルキル）、Ｎ（Ｃ_１〜３−アルキル）_２、Ｃ_１〜３−アルキル、フルオロ−Ｃ_１〜３−アルキル、ＯＨ、Ｃ_１〜３−アルコキシ、フルオロ−Ｃ_１〜３−アルコキシ、Ｃ_３〜６−シクロアルキルおよびフルオロ−Ｃ_３〜６−シクロアルキルから選択される基で１または２回、任意選択で置換されており、
Ｒ^１は、Ｃ_１〜４−アルキルおよびＣ_３〜６−シクロアルキルからなる群から選択され、ここで、Ｃ_１〜４−アルキルは、非置換であるか、またはフルオロ、ヒドロキシ、Ｃ_１〜３−アルコキシおよびフルオロ−Ｃ_１〜３−アルコキシからなる群から独立に選択される１から３個の置換基で置換されており、そしてＣ_３〜６−シクロアルキルは非置換であるか、またはフルオロ、ヒドロキシ、Ｃ_１〜３−アルキル、フルオロ−Ｃ_１〜３−アルキル、Ｃ_１〜３−アルコキシおよびフルオロ−Ｃ_１〜３−アルコキシからなる群から独立に選択される１から３個の置換基で置換されており、
Ｒ^２およびＲ^３は、水素、ハロゲン、Ｃ_１〜３−アルキル、ハロ−Ｃ_１〜３−アルキル、Ｃ_１〜３−アルコキシ、ハロ−Ｃ_１〜３−アルコキシ、シクロプロピルおよびフルオロ−シクロプロピルからなる群から独立に選択され、
Ｒ^４は、ハロゲン、Ｃ_１〜３−アルキル、ハロ−Ｃ_１〜３−アルキル、Ｃ_１〜３−アルコキシ、ハロ−Ｃ_１〜３−アルコキシ、Ｃ_３〜６−シクロアルキル、Ｃ_１〜３−アルキレン−Ｏ−Ｃ_１〜３−アルキルおよびフルオロ−Ｃ_３〜６−シクロアルキルからなる群から独立に選択され、
Ｒ^５は、水素、フルオロ、ＣＨ_３、ＣＨＦ_２およびＣＦ_３からなる群から選択され、
ｎは、０、１、２、３および４から選択され、
ｘは、０、１および２から独立に選択される］。 Accordingly, the present invention provides a compound according to the following formula (1), its enantiomer, diastereomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt:

[Where:
R is hydrogen, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, halo-C _1-6 -alkyl, C _0-6 -alkylene-R ⁷ , C _{0- 6} -alkylene-O—R ⁷ , C _0-6 -alkylene-CN, C _0-6 -alkylene-NR ⁷ R ⁸ , O—C _3-10 -cycloalkyl, O—C _1-6 -alkylene-O -R ^7, _O-C 3~10 - _{heterocycloalkyl, C Less than six} - alkylene _-CO 2 ^R _{7, C 0~6} - alkylene _{^{-C (O) R 7, C}} 0~6 - alkylene -C ( _{^{O) NR 7 R 8, C}} 0~6 - alkylene ^{_{-C (O) NR 7 SO 2}} R 7, C 0~6 - alkylene ^{-N (R 7) C (O} ) R 7, C 0~6 - alkylene _{-SO x} -R ^7, _C 0~6 - alkylene _-SO 3 H, _{C 0 6} - alkylene ^{_{-SO 2 -NR 7 R 8, C}} 0~6 - alkylene ^{_{-SO 2 -NR 8 COR 7, C}} 0~6 - alkylene _{^{-N (R 7) SO 2 -R}} 8, and _{C 0 to 6} - alkylene _-SO 2 _{-C 3 to 10} - is selected from the group consisting of heterocycloalkyl,
Where alkylene, cycloalkyl, heterocycloalkyl and 5- or 6-membered heteroaryl are unsubstituted or halogen, CN, C _1-3 -alkyl, halo-C _1-3 -alkyl, OH, _{oxo, CO 2 H, SO 3 H} , O-C 1~3 - is substituted by one to four substituents selected from the group consisting of alkyl independently - alkyl and O- halo _{-C 1 to 3} ,
R ⁷ is hydrogen, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _0-6 -alkylene-C _3-8 -cycloalkyl, C _0-6 -alkylene-C _{3-8 -hetero.} Independently selected from the group consisting of cycloalkyl, 5 or 6 membered heteroaryl and phenyl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, phenyl and heteroaryl are unsubstituted or or halogen, CN, OH, _oxo, CO 2 _{H, C 1~3} - alkyl, halo _{-C 1 to 3} - alkyl, _{O-C 1 to 3} - alkyl, O- halo _{-C 1 to 3} - alkyl, SO Substituted with 1 to 6 substituents independently selected from the group consisting of ₃ H and SO ₂ -C _1-3 -alkyl,
R ⁸ is independently selected from the group consisting of hydrogen, C _1-6 -alkyl, halo-C _1-6 -alkyl and C _3-6 -cycloalkyl,
Alternatively, R ⁷ and R ⁸ together with the nitrogen to which they are attached contain a carbon atom and optionally contain 1 or 2 heteroatoms selected from O, S or N A 3- to 8-membered ring may be completed, wherein the ring is unsubstituted or from the group consisting of fluoro, OH, oxo, C _1-4 -alkyl and halo-C _1-4 -alkyl. Substituted with 1 to 4 independently selected substituents;
A is 6-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic containing 1-5 heteroatoms independently selected from the group consisting of N, O and S Or bicyclic heteroaryl, where aryl and heteroaryl are unsubstituted or OH, halogen, CN, O—C _1-6 -alkyl, O-halo-C _1-6 -alkyl Independently selected from the group consisting of C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-6 -cycloalkyl, C _5-6 -heterocycloalkyl and halo-C _3-6 -cycloalkyl Substituted with 1 or 2 groups
Q is a C _3-10 -cycloalkyl ring, or a C _{5-10 -bridged} cycloalkyl ring, and the —O—CH ₂ —Z-substituent is not directly adjacent to substituent A, and Q is When it is a bicyclic or polycyclic ring system, the carbon atom may be optionally replaced with oxygen, SO _x or NR ⁷ ,
Z is

In the formula selected from
L is selected from the group consisting of a bond, C _1-3 -alkylene and C _1-3 -alkylene-O—
Y is selected from the group consisting of phenyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C _4-8 -cycloalkyl or C _4-8 -heterocycloalkyl, wherein phenyl, pyridyl, pyridyl -N- oxide, pyrimidyl, pyridinonyl, _{pyrimidinonyl, C 4 to 8} - cycloalkyl and _{C 4 to 8} - heterocycloalkyl is substituted with ^{R 2} and ^{R 3,} fluoro, chloro, _CN, NH 2, NH (C _1-3 -alkyl), N (C _1-3 -alkyl) ₂ , C _1-3 -alkyl, fluoro-C _1-3 -alkyl, OH, C _1-3 -alkoxy, fluoro-C _{1- 3} - _{alkoxy, C 3 to 6} - cycloalkyl and fluoro _{-C 3 to 6} - with a group selected from cycloalkyl Or twice, it is optionally substituted,
R ¹ is selected from the group consisting of C _1-4 -alkyl and C _3-6 -cycloalkyl, wherein C _1-4 -alkyl is unsubstituted or fluoro, hydroxy, C _{1- 3} - alkoxy and fluoro -C _{1 to 3 -} are substituted with one to three substituents independently selected from the group consisting of alkoxy, and C _{3 to 6 -} or cycloalkyl is unsubstituted, or 1 to 3 substitutions independently selected from the group consisting of fluoro, hydroxy, C _1-3 -alkyl, fluoro-C _1-3 -alkyl, C _1-3 -alkoxy and fluoro-C _1-3 -alkoxy Substituted with a group,
R ² and R ³ are hydrogen, halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, cyclopropyl and fluoro-cyclopropyl Independently selected from the group consisting of
R ⁴ is halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, C _3-6 -cycloalkyl, C _1-3 Independently selected from the group consisting of -alkylene-O-C _1-3 -alkyl and fluoro-C _3-6 -cycloalkyl;
R ⁵ is selected from the group consisting of hydrogen, fluoro, CH ₃ , CHF ₂ and CF ₃ ;
n is selected from 0, 1, 2, 3 and 4;
x is independently selected from 0, 1 and 2.]

  In another embodiment, the present invention is directed to a compound according to formula (1) as a medicament.

  In a further embodiment, the present invention relates to compounds according to formula (1) for use in the prevention and / or treatment of diseases mediated by FXR.

  In yet a further embodiment, the present invention is directed to the use of a compound according to formula (1) for the preparation of a medicament for the prevention and / or treatment of diseases mediated by FXR.

  In another embodiment, the invention provides a method for treating or preventing a disease mediated by FXR in a subject in need thereof, comprising administering an effective amount of a compound of formula (1) to the subject. Relates to a method comprising:

  In a preferred embodiment in combination with any of the above or below embodiments, the disease mediated by FXR is chronic intrahepatic or some form of extrahepatic cholestasis; liver fibrosis; liver obstruction Or chronic inflammatory disorders; cirrhosis; fatty liver and related syndromes, cholestasis or fibrosis effects associated with alcohol-induced cirrhosis or virus-mediated forms of hepatitis; liver failure or hepatic ischemia after extensive hepatectomy Selected from chemotherapy-related steatohepatitis (CASH); acute liver failure; and / or inflammatory bowel disease.

  In an equally preferred embodiment in combination with any of the above or below embodiments, the disease is a lipid and lipoprotein disorder; type II diabetes and diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and clinically distinct Clinical complications of type I and type II diabetes, including other observed effects of long-term diabetes; chronic organs due to forced accumulation of lipids, specifically triglycerides and subsequent activation of the profibrotic pathway Conditions and diseases resulting from fat and fibrotic degeneration, such as nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH); obesity or metabolic syndrome (dyslipidemia, diabetes or abnormally high Complex state of body mass index); and / or chronic obstructive atherosclerosis Acute myocardial infarction occurs as endpoints, is selected from acute stroke, or thrombosis.

  In another preferred embodiment in combination with any of the above or below embodiments, the disease is a non-malignant hyperproliferative disorder and a malignant hyperproliferative disorder, specifically hepatocellular carcinoma, colon adenoma and polyposis, colon Selected from adenocarcinoma, breast cancer, pancreatic adenocarcinoma, Barrett's esophagus or other forms of neoplastic disease of the gastrointestinal tract and liver.

  The compounds of the present invention share a common chemical structure according to formula (1) of claim 1.

In preferred embodiments in combination with any of the above or below embodiments, R of formula (1) is CO ₂ H, SO ₃ H, CONR ⁷ R ⁸ , tetrazolyl, 1,2,4-oxadiazole-5. (4H) - is selected from the group consisting of on-3-yl and _SO 2 NHCOR ^7.

In further preferred embodiments in combination with any of the above or below embodiments, R ⁷ of formula (1) is hydrogen, C _1-6 alkyl, halo-C _1-6 alkyl, C _1-6 alkylene-R ^9. And independently selected from the group consisting of SO ₂ -C _1-6 alkyl, wherein R ⁹ is selected from the group consisting of COOH, OH and SO ₃ H.

In preferred embodiments in combination with any of the above or below embodiments, R ⁸ of formula (1) is selected from the group consisting of hydrogen, C _1-6 alkyl and halo-C _1-6 alkyl.

  In an equally preferred embodiment in combination with any of the above or below embodiments, A is phenyl, pyridyl, pyrimidyl, pyrazolyl, indolyl, thienyl, benzothienyl, indazolyl, benzoisoxazolyl, benzoisothiazolyl, triazolo Selected from the group consisting of pyridinyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, oxadiazolyl, oxazolyl, naphthyl, quinolyl, isoquinolyl and benzoimidazolyl, where A is non-defined as defined above It may be substituted or may be substituted.

  In a more preferred embodiment in combination with any of the above or below embodiments, A is selected from the group consisting of phenyl, pyridyl, indolyl, indazolyl, benzisothiazolyl, triazolopyridinyl, benzothiazolyl, thiazolyl, oxazolyl, quinolyl. Where A may be unsubstituted or substituted as defined above.

In another preferred embodiment, A is selected from the group consisting of phenyl, pyridyl, indolyl, indazolyl, benzisothiazolyl, triazolopyridinyl, benzothiazolyl, thiazolyl, oxazolyl, quinolyl, each of which is unsubstituted Or OH, halogen, CN, O—C _1-6 -alkyl, O-halo-C _1-6 -alkyl, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _{3-6 -cyclo} Substituted with one or two groups independently selected from the group consisting of alkyl and halo-C _3-6 -cycloalkyl.

から選択される。 In preferred embodiments in combination with any of the above or below embodiments, R-A is

Selected from.

から選択される。 In a more preferred embodiment in combination with any of the above or below embodiments, R-A is

Selected from.

から選択される
［式中、
Ｌは、結合、Ｃ_１〜３−アルキレンおよびＣ_１〜３−アルキレン−Ｏ−からなる群から選択され、
Ｘは、ＣＨ、ＣＦ、ＮおよびＮＯからなる群から選択され、
Ｒ^１は、Ｃ_１〜４−アルキルおよびＣ_３〜６−シクロアルキルからなる群から選択され、ここで、Ｃ_１〜４−アルキルは、非置換であるか、またはフルオロ、ヒドロキシ、Ｃ_１〜３−アルコキシおよびフルオロ−Ｃ_１〜３−アルコキシからなる群から独立に選択される１から３個の置換基で置換されており、Ｃ_３〜６−シクロアルキルは、非置換であるか、またはフルオロ、ヒドロキシ、Ｃ_１〜３−アルキル、フルオロ−Ｃ_１〜３−アルキル、Ｃ_１〜３−アルコキシおよびフルオロ−Ｃ_１〜３−アルコキシからなる群から独立に選択される１から３個の置換基で置換されており、
Ｒ^２およびＲ^３は、水素、ハロゲン、Ｃ_１〜３−アルキル、ハロ−Ｃ_１〜３−アルキル、Ｃ_１〜３−アルコキシ、ハロ−Ｃ_１〜３−アルコキシ、シクロプロピルおよびフルオロ−シクロプロピルからなる群から独立に選択され、
Ｒ^５は、水素、フルオロ、ＣＨ_３、ＣＨＦ_２およびＣＦ_３からなる群から選択される］。 In further preferred embodiments in combination with any of the above or below embodiments, Z is

[In the formula,
L is selected from the group consisting of a bond, C _1-3 -alkylene and C _1-3 -alkylene-O—
X is selected from the group consisting of CH, CF, N and NO;
R ¹ is selected from the group consisting of C _1-4 -alkyl and C _3-6 -cycloalkyl, wherein C _1-4 -alkyl is unsubstituted or fluoro, hydroxy, C _{1- 3} - alkoxy and fluoro -C _{1 to 3 -} are substituted with one to three substituents independently selected from the group consisting of alkoxy, C _{3 to 6 -} cycloalkyl, unsubstituted or 1 to 3 substitutions independently selected from the group consisting of fluoro, hydroxy, C _1-3 -alkyl, fluoro-C _1-3 -alkyl, C _1-3 -alkoxy and fluoro-C _1-3 -alkoxy Substituted with a group,
R ² and R ³ are hydrogen, halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, cyclopropyl and fluoro-cyclopropyl Independently selected from the group consisting of
R ⁵ is selected from the group consisting of hydrogen, fluoro, CH ₃ , CHF ₂ and CF ₃ ].

から選択される
（式中、Ｘ、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^５は上記のように定義される）。 In a more preferred embodiment in combination with any of the above or below embodiments, Z is

(Wherein X, R ¹ , R ² , R ³ and R ⁵ are defined as above).

  In more preferred embodiments in combination with any of the above or below embodiments, X is selected from the group consisting of CH, CF, N and NO, and even more preferred X is selected from the group consisting of CH, N and NO. The

In a more preferred embodiment in combination with any of the above or below embodiments, R ¹ is selected from the group consisting of methyl, CF ₃ , CHF ₂ , isopropyl and cyclopropyl, wherein isopropyl and cyclopropyl are unsubstituted Or even more preferred, R ¹ is selected from the group consisting of isopropyl and cyclopropyl, wherein isopropyl and cyclopropyl are substituted with 1 or 2 fluoro or 1 hydroxy Is unsubstituted or substituted with 1 or 2 fluoro or 1 hydroxy.

In a more preferred embodiment in combination with any of the above or below embodiments, R ² is selected from the group consisting of fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ .
In an even more preferred embodiment in combination with any of the above or below embodiments, R ³ is selected from the group consisting of hydrogen, fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ .

In preferred embodiments in combination with any of the above or below embodiments, R ⁵ is selected from the group consisting of hydrogen, fluoro, CH ₃ , CHF ₂ and CF ₃ , more preferably R ⁵ is hydrogen.

は、

から選択される。 In preferred embodiments in combination with any of the above or below embodiments, the formula (1)

Is

Selected from.

は、

から選択され、
それぞれ、Ｒ^４で、任意選択で置換されており、
いっそうより好ましい

は、

である。 In a more preferred embodiment in combination with any of the above or below embodiments, the formula (1)

Is

Selected from
Each optionally substituted with R ⁴ ,
Even more preferred

Is

It is.

［式中、
Ａは、フェニル、ピリジル、ピリミジル、ピラゾリル、インドリル、チエニル、ベンゾチエニル、インダゾリル、ベンゾイソオキサゾリル、ベンゾイソチアゾリル、トリアゾロピリジニル、ベンゾフラニル、ベンゾトリアゾリル、フラニル、ベンゾチアゾリル、チアゾリル、オキサジアゾリル、オキサゾリル、ナフチル、キノリル、イソキノリル、ベンゾイミダゾリルからなる群から選択され、それぞれ、非置換であるか、またはＯＨ、ハロゲン、ＣＮ、Ｏ−Ｃ_１〜６−アルキル、Ｏ−ハロ−Ｃ_１〜６−アルキル、Ｃ_１〜６−アルキル、ハロ−Ｃ_１〜６−アルキル、Ｃ_３〜６−シクロアルキルおよびハロ−Ｃ_３〜６−シクロアルキルからなる群から独立に選択される１もしくは２個の基で置換されており、
Ｒは、ＣＯ_２Ｈ、ＳＯ_３Ｈ、ＣＯＮＲ^７Ｒ^８、テトラゾリル、１，２，４−オキサジアゾール−５（４Ｈ）−オン−３−イルおよびＳＯ_２ＮＨＣＯＲ^７からなる群から選択され、
Ｒ^７は、Ｈ、Ｃ_１〜６−アルキル、ハロ−Ｃ_１〜６−アルキル、Ｃ_１〜６−アルキレン−Ｒ^９およびＳＯ_２−Ｃ_１〜６−アルキルからなる群から選択され、
Ｒ^８は、Ｈ、Ｃ_１〜６−アルキル、ハロ−Ｃ_１〜６−アルキルからなる群から選択され、
Ｒ^９は、ＣＯＯＨ、ＯＨおよびＳＯ_３Ｈからなる群から選択され、
Ｚは、

から選択され、
Ｘは、ＣＨ、ＮおよびＮＯからなる群から選択され、
Ｒ^１は、メチル、イソプロピルおよびシクロプロピルからなる群から選択され、ここで、イソプロピルおよびシクロプロピルは、非置換であるか、あるいは１もしくは２個のフルオロまたは１個のヒドロキシで置換されており、
Ｒ^２は、フルオロ、クロロ、ＣＨ_３、ＣＨＦ_２、ＣＦ_３、ＯＣＨＦ_２およびＯＣＦ_３からなる群から選択され、
Ｒ^３は、水素、フルオロ、クロロ、ＣＨ_３、ＣＨＦ_２、ＣＦ_３、ＯＣＨＦ_２およびＯＣＦ_３からなる群から選択される］。 In a further preferred embodiment, the compounds of the invention are according to formula (2)

[Where:
A is phenyl, pyridyl, pyrimidyl, pyrazolyl, indolyl, thienyl, benzothienyl, indazolyl, benzisoxazolyl, benzisothiazolyl, triazolopyridinyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, Selected from the group consisting of oxadiazolyl, oxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, each unsubstituted or OH, halogen, CN, O—C _1-6 -alkyl, O-halo-C _1-6 1 or 2 independently selected from the group consisting of -alkyl, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-6 -cycloalkyl and halo-C _3-6 -cycloalkyl Substituted with a group,
R is selected from the group consisting of CO ₂ H, SO ₃ H, CONR ⁷ R ⁸ , tetrazolyl, 1,2,4-oxadiazol-5 (4H) -on-3-yl and SO ₂ NHCOR ⁷ ;
R ⁷ is selected from the group consisting of H, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _1-6 -alkylene-R ⁹ and SO ₂ -C _1-6 -alkyl;
R ⁸ is selected from the group consisting of H, C _1-6 -alkyl, halo-C _1-6 -alkyl,
R ⁹ is selected from the group consisting of COOH, OH and SO ₃ H;
Z is

Selected from
X is selected from the group consisting of CH, N and NO;
R ¹ is selected from the group consisting of methyl, isopropyl and cyclopropyl, wherein isopropyl and cyclopropyl are unsubstituted or substituted with 1 or 2 fluoro or 1 hydroxy;
R ² is selected from the group consisting of fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ ;
R ³ is selected from the group consisting of hydrogen, fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ ].

またはそのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、プロドラッグもしくは薬学的に許容される塩からなる群から選択される。 In preferred embodiments in combination with any of the above or below embodiments, the compound is

Or selected from the group consisting of enantiomers, diastereomers, tautomers, solvates, prodrugs or pharmaceutically acceptable salts thereof.

In the context of the present invention, “C _1-6 -alkyl” means a saturated alkyl chain having 1 to 6 carbon atoms, which may be straight or branched. Examples include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl.

The term “halo-C _1-6 -alkyl” means that one or more hydrogen atoms are replaced with halogen in the alkyl chain. Preferred examples thereof is CF _3.

“C _2-6 -alkenyl” means an alkyl chain having from 1 to 6 carbon atoms, which may be straight or branched, containing at least one carbon-carbon double bond. Examples thereof are ethenyl, propenyl, butenyl, pentenyl, hexenyl or (1E, 3Z) -2-methylpenta-1,3-dien-1-yl. Preferred examples are ethenyl, propenyl or (1E, 3Z) -2-methylpenta-1,3-dien-1-yl.

“C _2-6 -alkynyl” means an alkyl chain having from 1 to 6 carbon atoms, which may be straight or branched, containing at least one carbon-carbon triple bond. Examples thereof include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl or 3-hexynyl. Preferred examples thereof include ethynyl and propynyl.

“C _0-6 -alkylene” means that each group is divalent and connects the attached residue to the rest of the molecule. Further, in the context of the present invention, “C ₀ -alkylene” is intended to represent a bond.

A _C4-10 -cycloalkyl group means a saturated or partially unsaturated monocyclic, bicyclic or spirocyclic ring system containing 4 to 10 carbon atoms. A bridged carbocyclic ring system includes two or more ring systems that share non-adjacent bridgehead ring atoms. Examples include cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octanyl, spiro [3.3] heptyl, bicyclo [2.2.1] heptyl, adamantyl and Pentacyclo [4.2.0.0 ^2,5 . 0 ^3,8 . 0 ^4,7 ] octyl.

A C _3-10 -heterocycloalkyl group is a saturated or partially unsaturated 3-10 membered, wherein 1, 2 or 3 carbon atoms are replaced by 1, 2 or 3 heteroatoms, respectively. A monocyclic, bicyclic or spirocyclic ring of carbons, the heteroatoms being independently selected from N, O, S, SO and SO ₂ . Examples include epoxydyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1,4-dihydropyridinyl and 3,6-dihydro-2H- Thiopyranyl is mentioned. The C _3-10 -heterocycloalkyl group may be linked to the remainder of the molecule via a carbon atom or via a nitrogen atom.

である。 A 5- to 10-membered monocyclic or bicyclic heteroaromatic system containing up to 4 heteroatoms (also referred to in this application as heteroaryl) is a monocyclic heteroaromatic such as pyrrolyl, It means imidazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl and thiadiazolyl. This further implies a bicyclic ring system in which the heteroatom (s) may be present in one or both rings containing bridgehead atoms. Examples include quinolinyl, isoquinolinyl, quinoxalinyl, benzimidazolyl, benzoisoxazolyl, benzofuranyl, benzoxazolyl, indolyl, indolizinyl and pyrazolo [1,5-a] pyrimidinyl. The nitrogen or sulfur atom of the heteroaryl system may also be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Unless otherwise stated, heteroaryl systems may be linked via a carbon atom or via a nitrogen atom. An example for an N-linked heterocycle is

It is.

  A 6-10 membered monocyclic or bicyclic aromatic ring system (also referred to in this application as aryl) means an aromatic carbocycle, such as phenyl or naphthalenyl.

The term “N-oxide” refers to a compound in which the nitrogen in the heteroaromatic system (preferably pyridinyl) is oxidized. Such compounds can be obtained in a known manner by reacting the compounds of the invention (eg in the pyridinyl group) with H ₂ O ₂ or peracid in an inert solvent.

  The halogen is selected from fluorine, chlorine, bromine and iodine, more preferably fluorine or chlorine, most preferably fluorine.

Furthermore, the compounds of the invention are partly under the influence of tautomerism. For example, if a heteroaromatic group containing a nitrogen atom in the ring is substituted with a hydroxy group on a carbon atom adjacent to the nitrogen atom, the following tautomerism may occur:

が可能である。 _{AC 3-10} -cycloalkyl group means a saturated or partially unsaturated monocyclic, bicyclic spirocyclic or polycyclic ring system containing 5 to 10 carbon atoms. C _3-10 -heterocycloalkyl groups can be linked linearly or spirocyclically, for example, when cyclohexane is substituted with a heterocycloalkyl group oxetane, the following structure:

Is possible.

  If the list of alternative substituents includes members that cannot be used to substitute a particular group due to these valence requirements or other reasons, this list should be known to those skilled in the art. The skilled artisan understands that it is intended to be read as including only those members of the list that are suitable for substituting this particular group.

  The compounds of the present invention can be in the form of a prodrug compound. A “prodrug compound” is a derivative that is converted to a compound according to the present invention by reaction with an enzyme, gastric acid, etc. under physiological conditions of a living body, for example, by oxidation, reduction, hydrolysis, etc., respectively performed by the enzyme. Means. Examples of prodrugs are those wherein the amino group in the compounds of the invention is acylated, alkylated or phosphorylated to form, for example, eicosanoylamino, alanylamino, pivaloyloxymethylamino, or the hydroxyl group is Acylated, alkylated, phosphorylated or converted to borate (eg acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy), or the carboxyl group is esterified or amidated It is a compound. These compounds can be produced from the compounds of the present invention according to well-known methods. Other examples of prodrugs are compounds in which the carboxylate in the compounds of the invention has been converted to, for example, alkyl-, aryl-, choline-, amino, acyloxymethyl esters, linolenoyl esters.

  In human liver, UDP-glucuronosyltransferase acts on certain compounds with amino, carbamyl, thio (sulfhydryl) or hydroxyl groups to uridine diphosphate-α-D-glucuronic acid via glycosidic bonds. Conjugate or esterify compounds with carboxy or hydroxyl groups in the phase II metabolic process. The compounds of the present invention are capable of forming glucuronidation, i.e., can be conjugated to glucuronic acid to form glucuronides, particularly (β-D) glucuronides.

  Metabolites of the compounds of the invention are also within the scope of the invention.

  One step in the formation of bile is the conjugation of individual bile acids with amino acids, particularly glycine or taurine. The compounds of the invention can be conjugated with glycine or taurine at substitutable positions.

  Where tautomerism of the compounds of the invention or their prodrugs can occur, such as keto-enol tautomerism, the individual forms, such as keto and enol forms, and mixtures of these in any ratio are Each is within the scope of the present invention. The same applies to stereoisomers such as enantiomers, cis / trans isomers, conformers and the like.

  If desired, isomers can be separated by methods well known in the art, for example, by liquid chromatography. The same applies to enantiomers, for example by using chiral stationary phases. In addition, enantiomers are isolated by converting them to diastereomers, ie by coupling with enantiomerically pure auxiliary compounds, then separating the resulting diastereomers and cleaving the auxiliary residues. can do. Alternatively, any enantiomer of a compound of the invention can be obtained from stereoselective synthesis using optically pure starting materials. Another scheme for obtaining pure enantiomers from racemic mixtures uses enantioselective crystallization with chiral counterions.

  The compounds of the present invention can be in the form of pharmaceutically acceptable salts or solvates. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids. Where the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically usable Salt. Thus, the compounds of the invention containing acidic groups can be present on these groups and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. There can be compounds of the invention which contain one or more basic groups, ie groups which can be protonated, and are used according to the invention in the form of their addition salts with inorganic or organic acids. be able to. Examples of suitable acids include hydrogen chloride, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, Formic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, Citric acid, adipic acid, and other acids known to those skilled in the art. When the compounds of the invention contain both acidic and basic groups in the molecule, the invention also includes intramolecular salts or betaines (zwitterions) in addition to the described salt forms. Each salt is contacted with an organic or organic base or inorganic or inorganic base in a customary manner known to those skilled in the art, for example in a solvent or dispersant, or anion exchange with other salts. Alternatively, it can be obtained by cation exchange. The present invention is also not suitable for use in medicine as it is due to its low physiological compatibility, but is used as an intermediate, for example, for chemical reactions or for the preparation of pharmaceutically acceptable salts. Also included are all salts of the compounds of the present invention that can.

  Furthermore, the compounds of the present invention may be used in the form of solvates, for example, as solvates containing water, or as pharmaceutically acceptable solvates, for example, solvents containing alcohol, especially ethanol and the like. It may exist as a Japanese product.

  Furthermore, the present invention comprises as active ingredient at least one compound of the present invention, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutically acceptable carrier. A pharmaceutical composition is provided.

  A “pharmaceutical composition” is a combination, complexation or aggregation of one or more active ingredients and one or more inactive ingredients that make up the carrier, and any two or more ingredients, or 1 Any product produced directly or indirectly from the dissociation of one or more components, or from other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention and a pharmaceutically acceptable carrier.

  The pharmaceutical compositions of the present invention may further comprise one or more other compounds as active ingredients such as prodrug compounds or other nuclear receptor modulators.

  The composition is suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration However, the most appropriate route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. These can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art.

  As a result, the present invention relates to compounds according to general formula (1) which bind to FXR and act as agonists or modulators of FXR.

  The invention further relates to the use of said compounds for the treatment and / or prevention of diseases and / or conditions through binding to said nuclear receptor by said compounds. Furthermore, the present invention relates to the use of said compounds for the preparation of a medicament for the treatment and / or prevention of diseases and / or conditions through binding to said nuclear receptor by said compounds. Specifically, the present invention relates to obstructive properties resulting from chronic intrahepatic or some forms of extrahepatic cholestatic conditions, liver fibrosis, acute intrahepatic cholestatic conditions, inappropriate bile composition. Or chronic inflammatory disorders, gastrointestinal conditions with reduced intake of dietary fat and dietary fat-soluble vitamins, inflammatory bowel disease, lipid and lipoprotein disorders, type II diabetes, and clinical practice of type I and type II diabetes Conditions and diseases resulting from chronic complications of lipids, specifically forced accumulation of triglycerides and subsequent activation of the pro-fibrotic pathway, and chronic fat and fibrotic degeneration of the organs, obesity and metabolic syndrome (dyslipidemia) As a composite state of diabetes, abnormally high body mass index), acute myocardial infarction, acute stroke, chronic obstructive atherosclerosis Live thrombosis, persistent infection with intracellular bacteria or parasite protozoa, non-malignant hyperproliferative disorder, malignant hyperproliferative disorder, especially colon adenocarcinoma and hepatocellular carcinoma, fatty liver and related syndromes, chronic liver disease Or cholestasis and fibrosis associated with liver failure or liver dysfunction as a result of surgical hepatectomy, hepatitis B infection, hepatitis C infection and / or alcohol-induced cirrhosis or virus-mediated form of hepatitis It relates to the use of a compound according to formula (1) in the preparation of a medicament for the prevention and / or treatment of crystallization effects.

  A medicament as referred to herein comprising a combination of a compound according to the invention and a pharmaceutically acceptable carrier can be prepared by conventional processes.

  FXR has been proposed to be a nuclear bile acid sensor. As a result, FXR modulates both the amount of bile acids synthesized in the liver (by modulating bile acid binding proteins) and their recycling in the intestine. However, besides bile acid physiology, FXR is a form of cholesterol gallstones, metabolic disorders such as type II diabetes, dyslipidemia or obesity, chronic inflammatory diseases such as inflammatory bowel disease, or chronic intrahepatic forms. It appears to be involved in the regulation of many diverse physiological processes related to the cause and treatment of a wide variety of diseases such as cholestasis and many other diseases (T. Claudel et al., Arterioscler. Thromb. Vasc. Biol., 2005, 25, 2020; YD Wang et al., Cell Res., 2008, 18, 1087).

  FXR regulates a complex pattern of response genes in the liver and gastrointestinal tract. Gene products affect a variety of physiological processes. During the functional analysis of FXR, the first regulatory network analyzed was the regulation of bile acid synthesis. LXR induces Cyp7A1, a major enzyme that converts cholesterol to bile acids, via induction of the regulatory nuclear receptor LRH-1, whereas FXR is a more potent inhibitor than LRH-1 Suppresses induction of Cyp7A1 through upregulation of mRNA encoding the internal receptor SHP. Since FXR binds to the end product of this pathway, primary bile acids such as cholic acid (CA) or CDCA, this can be considered as an example of feedback inhibition on gene expression levels (B Goodwin et al., Mol. Cell, 2000, 6, 517; TT Lu et al., Mol. Cell, 2000, 6, 507). In parallel with SHP-mediated inhibition of bile acid synthesis, FXR is a series of so-called ABCs that are involved in the export of toxic bile acids from hepatocyte cytosol to tubules, which are small bile duct branches that produce bile. Trigger transporters (for ATP binding cassettes). This hepatoprotective function of FXR was first revealed in an analysis of FXR knockout mice (CJ Sinal et al., Cell, 2000, 102, 731), in which some ABC transporters in the liver were underdeveloped. Expression or overexpression was indicated. By further detailed analysis, the major bile salt excretion pump BSEP or ABCB11 (M. Ananthanarayanan et al., J. Biol. Chem. 2001, 276, 28857; JR Plass et al., Hepatology, 2002, 35, 589 ) And the major enzyme that mediates lipid transfer from lipoproteins to phospholipids, PLTP (NL Urizar et al., J. Biol. Chem. 2000, 275, 39313), and two types for phospholipids Major tubule membrane transporters, MRP-2 (ABCC4) (HR Kast et al., J. Biol. Chem., 2002, 277, 2908) and MDR-3 (ABCB4); L. Huang et al., J. Biol Chem., 2003, 278, 51085) has been shown to be a direct target for ligand-directed transcriptional activation by FXR (M. Miyat a. J. Pharmacol. Exp. Ther., 2005, 312, 759; G. Rizzo et al., Curr. Drug Targets Immune Endocr. Metabol. Disord., 2005, 5, 289. ).

  The fact that FXR is a major metabolite sensor and appears to be a regulator for bile acid synthesis, export and recirculation induces bile flow and further changes bile acid composition to a hydrophilic composition Suggests the use of FXR ligands for First synthetic FXR ligand GW4064 as a tool compound (PR Maloney et al., J. Med. Chem., 2000, 43, 2971; TM Willson et al., Med. Res. Rev., 2001, 21, 513) ) And the development of the semi-synthetic artificial bile acid ligand 6-alpha-ethyl-CDCA, it was possible to analyze the effects of over-stimulation of FXR by potent agonists. Both ligands have been shown to induce bile flow in animals ligated with bile ducts. Furthermore, in addition to the biliary secretion promoting action, hepatoprotective action could also be demonstrated (R. Pellicciari et al., J. Med. Chem., 2002, 45, 3569; Y. Liu et al., J. Clin. Invest., 2003, 112, 1678). This hepatoprotective action was further narrowed down to antifibrotic action, but this antifibrotic action was inhibited by a matrix-metalloproteinase tissue inhibitor, TIMP-1 and 2, and in liver stellate cells by FXR agonists. Results from the induction of collagen deposition-degrading matrix metalloproteinase 2 and subsequent reduction of alpha-collagen mRNA and transforming growth factor beta (TGF-beta) mRNA, both of which promote fibrosis (S. Fiorucci) Gastroenterology, 2004, 127, 1497; S. Fiorucci et al., J. Pharmacol. Exp. Ther., 2005, 314, 584). Furthermore, anti-cholestatic activity has been demonstrated in animal models with bile duct ligation as well as in animal models of estrogen-induced cholestasis (S. Fiorucci et al., J. Pharmacol. Exp. Ther., 2005, 313 Volume, page 604).

  Genetic studies show that in hereditary forms of cholestasis (progressive familial intrahepatic cholestasis = PFIC, types I-IV), the nuclear localization of FXR itself as a result of mutations in the FIC1 gene Decrease (PFICI type, also called Baylor disease) (F. Chen et al., Gastroenterology, 2004, 126, 756; L. Alvarez et al., Hum. Mol. Genet., 2004, 13, 2451) ) Or the level of FXR target gene encoding the MDR-3 phospholipid export pump has been demonstrated (PFICIII type). Taken together, FXR binding compounds have considerable clinical utility in therapeutic regimens such as chronic cholestatic conditions, such as primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). There is an increasing number of evidence to be demonstrated (G. Rizzo et al., Curr. Drug Targets Immune Endocr. Metabol. Disord., 2005, 5, 289; G. Zollner et al., Mol. Pharm. 2006, volume 3, page 231; SY Cai et al., Expert Opin. Ther. Targets, 2006 volume 10, page 409).

  The tremendous effect FXR activation has on bile acid metabolism and excretion is not only related to cholestatic syndrome, but more directly to therapy for gallstone formation. Cholesterol gallstones form because of the low solubility of cholesterol that is actively pumped from liver cells into the lumen of tubules. It is the relative percentage of the content of the three main components, bile acid, phospholipid and free cholesterol that determines the formation of mixed micelles and thus the apparent solubility of free cholesterol in bile. The FXR polymorphism maps as a quantitative trait locus as one factor contributing to gallstone disease (H. Wittenburg, Gastroenterology, 2003, 125, 868). Using the synthetic FXR tool compound GW4064, activation of FXR results in improved cholesterol saturation index (CSI), directly leading to eradication of gallstone formation in C57L gallstone-sensitive mice whereas FXR knockout It was possible to demonstrate that drug treatment in mice has no effect on gallstone formation (A. Moschetta et al., Nature Medicine, 2004, 10, pp. 1352).

  From these results, FXR is a good target for the development of small molecule agonists that can be used to prevent cholesterol gallstone formation or to prevent gallstone remodeling after surgical resection or shock wave lithotripsy (Considered in SA Doggrell, Curr. Opin. Investig. Drugs, 2006, volume 7, page 344).

  Thus, in one embodiment of the invention, the compound according to formula (1) and the pharmaceutical composition comprising said compound are also known as obstructive or chronic inflammatory disorders resulting from inappropriate bile compositions, eg cholesterol gallstones Used for prevention and / or treatment of cholelithiasis and the like.

  In addition to its strong hepatoprotective and bile secretion-promoting effects and anti-fibrotic effects that FXR exhibits when activated by small molecule stimulation in the liver, FXR is also responsible for neoplastic transformation and polyp development in the intestine. And appears to have a role in protecting the intestine from metastasis to these adenocarcinomas (S. Modica et al., Cancer Res., 2008, 68, 9589 and RR Maran et al., J. Pharmacol. Exp. Ther. 2009, 328, 469). Similar to the intestinal situation, the absence of FXR results in a high increase in the formation of hepatocellular carcinoma (Cacrcinoma) (HCC), the most prominent form of liver cancer (I. Kim et al., Carcinogenesis, 2007, 28, 940 and F. Yang et al., Cancer Res., 2007, 67, 863). While functional FXR prevents colon adenocarcinoma and hepatocellular carcinoma formation, activation of FXR induces liver regeneration after hepatectomy (W. Huang et al., Science, 2006, 312). 233).

  The combination of hepatoprotective, anti-neoplastic and liver regeneration effects associated with FXR activation can be used therapeutically for the use of FXR agonists in the treatment of severe liver disease. In one embodiment, a compound according to the invention and a pharmaceutical composition comprising said compound are used to treat liver diseases such as HCC, stimulation of liver regrowth and alleviation of side effects associated with extensive hepatectomy, cirrhosis (regardless of cause) ), As well as prevention or treatment of liver ischemia in the course of liver transplantation or primary extensive liver surgery.

  Since the first synthetic FXR agonist was discovered and administered to rodents, FXR has been shown to be a major regulator of serum triglycerides (P. Maloney et al., J. Med. Chem., 2000, 43, 2971; T. Willson et al., Med. Res. Rev., 2001, 21, 513). There is published evidence accumulated over the past six years that activation of FXR by synthetic agonists not only results in a significant decrease in serum triglycerides, but also in the form of a decrease in VLDL, as well as a decrease in total serum cholesterol. (HR Kast et al., Mol. Endocrinol. 2001, 15: 1720; NL Urizar et al., Science, 2002, 296, 1703; G. Lambert et al., J. Biol. Chem., 2003, 278. 2563; M. Watanabe et al., J. Clin. Invest, 2004, 113, 1408; A. Figge et al., J. Biol. Chem., 2004, 279, 2790; S. Bilz et al. Am. J. Physiol. Endocrinol. Metab., 2006, 290, E716).

However, lowering serum triglycerides is not a single effect. Treatment of db / db or ob / ob mice with the synthetic FXR agonist GW4064 resulted in significant and combined decreases in serum triglycerides, total cholesterol, free fatty acids, ketone bodies such as 3-OH butyrate. Furthermore, FXR activation, coupled with the intracellular insulin signaling pathway in hepatocytes, decreases glucose release from hepatic gluconeogenesis, but at the same time increases liver glycogen. Insulin sensitivity and glucose tolerance were positively affected by FXR treatment (KR Stayrook et al., Endocrinology, 2005, 146, 984; Y. Zhang et al., PNAS, 2006, 103, 1006; B. Cariou et al., J. Biol. Chem., 2006, 281, 11039; K. Ma et al., J. Clin. Invest., 2006, 116, 1102; D. Duran-Sandoval et al., Biochimie, 2005. Year, 87, 93). An effect on weight loss was also recently observed in mice fed an overdose of high lipids (C. Lihong et al., American Diabetes Association (ADA) 66 ^th annual scientific sessions, June 2006, Abstract # 856-P). . This weight loss effect may result from FXR induction of fibroblast growth factor FGF-19, which is known to result in weight loss and a sports phenotype (J. Holt et al., Genes Dev., 2003, Vol. 17, 1581; E. Tomlinson et al., Endocrinology, 2002, 143, 1741). In a recent patent application, the effect of FXR agonists on weight loss has been demonstrated (WO 2004/087076; WO 2003/080803).

  Taken together, these pharmacological effects of FXR agonists can be utilized in a variety of therapeutic regimes. FXR binding compounds are thought to be potential candidates for the treatment of type II diabetes due to their insulin sensitizing, glycogenogenic, and lipid lowering effects.

  In one embodiment, a compound according to the invention and a pharmaceutical composition comprising said compound comprise systemic insulin sensitivity and FXR-mediated upregulation of intracellular insulin signaling in the liver, increased peripheral glucose uptake and metabolism, liver It is used for the prevention and / or treatment of type II diabetes that can be overcome by increasing glycogen storage in the body, reducing glucose release into the serum from liver-derived gluconeogenesis.

  In further embodiments, the compounds and pharmaceutical compositions comprise chronic intrahepatic cholestatic conditions such as PBC, PSC, progressive familial cholestasis (PFIC), alcohol-induced cirrhosis and related cholestasis, etc. As well as some forms of extrahepatic cholestatic conditions, or for the prevention and / or treatment of liver fibrosis.

  The present invention also provides a formula (1) for the prevention and / or treatment of gastrointestinal conditions with reduced uptake of dietary fat and dietary fat-soluble vitamins that can be overcome by increasing intestinal levels of bile acids and phospholipids. Or a pharmaceutical composition comprising said compound.

  In further embodiments, the compound or pharmaceutical composition comprises a reduction in total plasma cholesterol, a reduction in serum triglycerides, an increased conversion of liver cholesterol to bile acids in the liver, and clearance and metabolic properties of VLDL and other lipoproteins. From the group consisting of lipid and lipoprotein disorders such as hypercholesterolemia, hypertriglyceridemia, and atherosclerosis as clinically apparent conditions that can be reversed by the beneficial effects of FXR on increased conversion Used to prevent and / or treat selected diseases.

  In a further embodiment, the compounds and pharmaceutical compositions comprise a combination of FXR targeted pharmaceutical lipid lowering, anti-cholestatic and anti-fibrotic effects for the treatment of fatty liver and related syndromes such as NASH. Or used for the prevention and / or treatment of diseases that can be utilized for the treatment of cholestasis and fibrosis effects associated with alcohol-induced cirrhosis or with virus-mediated forms of hepatitis.

  In conjunction with the lipid lowering effect, loss of functional FXR has also been shown to result in increased atherosclerosis in ApoE knockout mice (EA Hanniman et al., J. Lipid Res., 2005, 46, 2595). Thus, FXR agonists may have clinical utility as anti-atherosclerotic and cardioprotective drugs. Down-regulation of endothelin-1 in vascular smooth muscle cells can also contribute to such beneficial therapeutic effects (F. He et al., Circ. Res., 2006, 98, 192).

  The present invention also provides a formula (1) for prophylactic and post-traumatic treatment of cardiovascular disorders that occur as endpoints of chronic obstructive atherosclerosis, such as acute myocardial infarction, acute stroke, or thrombosis. Or a pharmaceutical composition comprising said compound.

  In addition to controlling intestinal and colonic polyp formation, FXR appears to be expressed in breast cancer tissues and cell lines but not in healthy breast tissue and interacts with estrogen receptors in ER positive breast cancer cells. (KE Swales et al., Cancer Res., 2006, 66, 10120 and F. Journe et al., Breast Cancer Res. Treat., 2009, 115, 523).

  This also allows FXR to be considered a potential target for the treatment of proliferative diseases, particularly metastatic cancer forms that express small molecule responsive forms of FXR.

  In further embodiments, the compounds and pharmaceutical compositions may be of a certain form in which malignant hyperproliferative disorders, such as different forms of cancer, specifically, interference with FXR ligands will have beneficial effects. Used for prevention and / or treatment of breast cancer, liver cancer or colon cancer.

  Finally, FXR also appears to be involved in the control of antimicrobial defense in the gut (T. Inagaki et al., PNAS., 2006, 103, 3920), but the exact mechanism is provided It has not been. However, from these published data, treatment with FXR agonists is beneficial in the therapy of inflammatory bowel disease (IBD), particularly in forms where the upper intestinal (ileum) part is affected (eg, Crohn's disease of the ileum) It can be concluded that there is a possibility that it will have a significant impact. This is because this part is considered to be an action point of FXR control on bacterial growth. In IBD, desensitization of the adaptive immune response is somehow impaired in the intestinal immune system. Thus, bacterial overgrowth can trigger the establishment of a chronic inflammatory response. Therefore, reducing the momentum of bacterial growth through FXR-mediated mechanisms can be a major mechanism for preventing the development of acute inflammatory symptoms.

  Accordingly, the present invention also provides a compound according to formula (1) or a pharmaceutical composition comprising said compound for preventing and / or treating diseases related to inflammatory bowel disease, such as Crohn's disease or ulcerative colitis. Also related. FXR-mediated restoration of intestinal barrier function and reduction of the amount of non-symbiotic bacteria may help reduce exposure of bacterial antigens to the intestinal immune system and thus reduce the inflammatory response. It has been.

  The present invention relates to metabolic syndrome (dyslipidemia, diabetes and abnormalities) that can be overcome by obesity and related disorders such as FXR-mediated serum triglycerides, decreased blood glucose, and increased insulin sensitivity and FXR-mediated weight loss. It further relates to compounds or pharmaceutical compositions for the prevention and / or treatment of high body mass index complex conditions).

  In a further embodiment, the compounds or pharmaceutical compositions of the invention are useful for preventing and / or treating clinical complications of type I and type II diabetes. Examples of such complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, or peripheral artery occlusion disease (PAOD). Other clinical complications of diabetes are also encompassed by the present invention.

  In addition, conditions and diseases resulting from chronic fat and fibrotic degeneration of organs due to forced accumulation of lipids, specifically triglycerides and subsequent activation of the profibrotic pathway, are also included in the compounds or pharmaceutical compositions of the present invention. Can be prevented and / or treated. Such conditions and diseases include liver NASH and chronic cholestatic conditions, renal glomerulosclerosis and diabetic nephropathy, ocular retinal macular degeneration and diabetic retinopathy, and neurodegenerative diseases such as the brain Including Alzheimer's disease, or diabetic neuropathy of the peripheral nervous system.

  In practice, the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, eg, oral or parenteral (including intravenous). In the preparation of compositions for oral dosage forms, for example in the case of oral liquid preparations such as suspensions, elixirs and solutions, for example water, glycols, oils, alcohols, flavoring agents, preservatives Or in the case of oral solid preparations such as powders, hard and soft capsules and tablets, for example, starches, sugars, microcrystalline cellulose, diluents, granulating agents, Any of the usual pharmaceutical media such as lubricants, binders, disintegrants and the like can be utilized, and oral solid preparations are preferred over liquid preparations.

  Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions can, of course, vary and may conveniently be between about 2 percent and about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally, for example, as a liquid nasal spray or spray.

  Tablets, pills, capsules, etc. also have binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid Lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it may contain a liquid carrier such as fatty oil in addition to the above types of materials.

  Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

  Because it is well known that most of the compounds of the present invention correspond to carboxylic acids or similar anionic isosteres, and salt forms of ionic drug compounds can significantly affect the bioavailability of drug compounds. The compounds of the present invention can also be used as salts with various counter cations to yield orally available formulations. Such pharmaceutically acceptable cations include ammonium, alkali metal sodium or potassium or alkaline earth metal magnesium or calcium, certain pharmaceutically acceptable amines such as tris (hydroxy), among others. It may be a monovalent or divalent ion such as methyl) amino-methane, ethylenediamine, diethylamine, piperazine and the like, or certain cationic amino acids such as lysine or arginine.

  The compounds of the present invention can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersants can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

  Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of injectable sterile solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

  Any suitable route of administration can be utilized to provide a mammal, particularly a human, with an effective dose of a compound of the invention. For example, oral, rectal, topical, parenteral, eye, lung, nasal, and the like can be used. Examples of the dosage form include tablets, troches, dispersions, suspensions, liquids, capsules, creams, ointments, aerosols and the like. Preferably the compounds of the invention are administered orally.

  The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage can be ascertained readily by a person skilled in the art.

  When treating or preventing an FXR-mediated condition to which a compound of the invention is indicated, the compound of the invention is administered at a daily dosage of from about 0.1 milligrams to about 100 milligrams per kilogram of animal body weight Satisfactory results are generally obtained when given, preferably as a daily dose, or in divided doses from 2 to 6 times a day, or in sustained release form. For most large mammals, the total daily dose is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. For a 70 kg human adult, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.

  The compounds of the present invention can be prepared using the appropriate materials according to the procedures of the following schemes and examples and are further illustrated by the following specific examples. Furthermore, by utilizing the procedures described herein in conjunction with common knowledge in the art, additional compounds of the present invention claimed herein can be readily prepared. it can. However, the compounds illustrated in the examples are not to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that these compounds can be prepared using known variations of the conditions and processes of the following preparative procedures. The compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described above.

  The amine free base corresponding to the isolated salt can be neutralized with a suitable base such as aqueous sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, and the liberated amine free base into an organic solvent. It can be produced by extraction and subsequent evaporation. The amine free base thus isolated is further converted to another pharmaceutically acceptable salt by dissolution in an organic solvent, followed by addition of an appropriate acid, and subsequent evaporation, precipitation or crystallization. can do. The free carboxylic acid corresponding to the isolated salt is neutralized with a suitable acid such as aqueous hydrochloric acid, sodium hydrogen sulfate, sodium dihydrogen phosphate, etc., and the free free carboxylic acid is extracted into an organic solvent, This can be generated by subsequent evaporation. The carboxylic acid thus isolated is further converted to another pharmaceutically acceptable salt by dissolution in an organic solvent, followed by addition of a suitable base, and subsequent evaporation, precipitation or crystallization. be able to.

An illustration of the preparation of the compounds of the present invention is given below. Unless otherwise indicated in the scheme, the variables have the same meaning as described above. The examples presented below are intended to illustrate specific embodiments of the present invention. Suitable starting materials, building blocks and reagents utilized in the synthesis as described below are commercially available from, for example, Sigma-Aldrich or Acros Organics or from literature such as “March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure ”5th edition; John Wiley & Sons or T. Eicher, S. Hauptmann“ The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application ”2nd edition, Wiley-VCH 2003; Fieser et al.,“ Fiesers 'Reagents for organic synthesis', John Wiley & Sons, 2000, can be routinely prepared.
General scheme

The compounds of the present invention can be prepared according to Schemes 1-3. An alicyclic ring Q (1-1) carrying a ketal functional group and a hydroxyl group is alkylated with chloro- or bromomethyl heteroaromatic XCH ₂ Z in the presence of a strong base in a suitable solvent at a suitable temperature. The intermediate 1-2 can be obtained. The 1-2 ketal functionality can be deprotected under acidic conditions to form ketone 1-3. Intermediates 1-3 can be added to metallated aromatics or heteroaromatics to form hydroxyl-carrying intermediates 1-4, which can be converted to compounds of the invention at substituent R ′. Further conversion is possible.

More precisely, as depicted in Scheme 2, 1,4-dioxaspiro [4.5] decan-8-ol (2-1) is prepared in a suitable solvent in the presence of a strong base. Alkylation with chloro- or bromomethylheteroaromatic XCH ₂ Z at temperature can give intermediate 2-2. After deprotection under acidic conditions, cyclohexanone derivative 2-3 is formed. Intermediate 2-3 can add a metallated aromatic or heteroaromatic to form a hydroxyl-carrying cyclohexyl derivative 2-4, which has two oxygen substituents attached to each other cis of the cyclohexyl ring. Or it can be separated into two single isomers 2-4 ′ and 2-4 ″ in the trans position. Intermediates 2-4 ′ and 2-4 ″ can each be further converted to compounds of the present invention at substituent R ′.

In Scheme 3, a general synthetic scheme for the bicyclic linker element Q is shown. Which is a mixture of exo and endo isomer, bicyclic alcohol Int-5-2 in the presence of a strong base in a suitable solvent at a suitable temperature, chloro - or alkyl bromomethyl heteroaromatic XCH 2 _Z To give intermediates 3-2 and 3-2 ′, which can be separated by standard procedures such as, for example, flash chromatography on silica gel using an appropriate eluent. Cyclic ketal 3-2 can be deprotected under acidic conditions to produce bicyclic ketone 3-3, to which a metallated aromatic or heteroaromatic can be added to provide a hydroxyl-retaining intermediate. Form body 3-4. These can be further converted to the compounds of the present invention by performing standard reactions known to those skilled in the art at the substituent R ′. Endo isomer 3-2 ′ follows the same transformation as depicted for exo isomer 3-2 in Scheme 3 to yield the corresponding final compound of the endo isomer of the present invention.

List of abbreviations DMF dimethylformamide NCS N-chlorosuccinimide DCM dichloromethane THF tetrahydrofuran PE petroleum ether DMSO dimethyl sulfoxide IBX o-iodoxybenzoic acid DBU 1,8-diazabicyclo [5.4.0] undec-7-ene p-TsOH p- Toluenesulfonic acid TEA Triethylamine MsCl Mesyl chloride TFA Trifruoroacetic acid
DIAD azodicarboxylate diisopropyl DAST (dimethylamino) sulfur trifluoride TLC thin layer chromatography MeCN acetonitrile m-CPBA m-chloroperbenzoic acid SEM-Cl 2- (trimethylsilyl) ethoxymethyl chloride TFAA trifluoroacetic anhydride ACN acetonitrile TMS trimethylsilyl TEMPO 2,2,6,6-tetramethylpiperidinyloxyl, free radical PCC pyridinium perchromate
HMPA Hexamethylphosphonamide Dba Dibenzylidineacetone
Xanthophos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene EDCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride DMAP 4-dimethylaminopyridine

ステップ１：ＥｔＯＨ（７０ｍＬ）中の４，４−ジフルオロシクロヘキサンカルバルデヒド（７．０ｇ、４７．３ｍｍｏｌ）の溶液に、水（１８ｍＬ）中のＮＨ_２ＯＨ・ＨＣｌ（３．９ｇ、５６．７ｍｍｏｌ）およびＮａ_２ＣＯ_３（６．０ｇ、５６．７ｍｍｏｌ）の混合物を添加した。混合物を室温で２時間にわたって撹拌し、水（２００ｍＬ）で希釈し、ＥｔＯＡｃ（３×５０ｍＬ）で抽出した。合わせた有機層をブライン（５０ｍＬ）で洗浄し、乾燥させ、濾過し、濃縮して、４，４−ジフルオロシクロヘキサンカルバルデヒドオキシムＩｎｔ−１ａ−１を生じさせた。 Intermediate Int-1-1: (5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methanol

Step 1: EtOH (70mL) solution of 4,4-difluoro-cyclohexane-carbaldehyde (7.0 g, 47.3 mmol) to a solution of water (18 mL) solution of _{NH 2 OH · HCl (3.9g,} 56.7mmol) And a mixture of Na ₂ CO ₃ (6.0 g, 56.7 mmol) was added. The mixture was stirred at room temperature for 2 hours, diluted with water (200 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried, filtered and concentrated to give 4,4-difluorocyclohexanecarbaldehyde oxime Int-1a-1.

  Step 2: To a solution of 4,4-difluorocyclohexanecarbaldehyde oxime Int-1a-1 (1.0 g, 6.2 mmol) in DMF (10 mL) was added NCS (1.0 g, 7.4 mmol). The reaction was stirred at room temperature for 1 hour, diluted with water and extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine (2 × 100 mL), dried, filtered and concentrated to give 4,4-difluoro-N-hydroxycyclohexanecarbimidoyl chloride Int-1b-1. Used without further purification.

Step 3: To a solution of methyl 3-cyclopropyl-3-oxopropanoate (1.3 g, 9.3 mmol) in THF (60 mL) is added Et ₃ N (6.3 g 62 mmol) and the reaction is allowed to reach room temperature. For 30 minutes, then 4,4-difluoro-N-hydroxycyclohexanecarbimidoyl chloride Int-1b-1 in THF was added dropwise. The resulting mixture was stirred at room temperature for 2 hours, evaporated and the residue was partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was washed with brine, dried, filtered, concentrated and purified by column chromatography (PE / EtOAc = 10: 1) to give methyl 5-cyclopropyl-3- (4,4-difluorocyclohexyl). Isoxazole-4-carboxylate Int-1c-1 was generated.

Step 4: To a solution of methyl 5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazole-4-carboxylate Int-1c-1 (3.9 g, 13.7 mmol) in THF (39 mL) LiAlH ₄ (27.4 mL, 27.4 mmol, 1M in THF) was added dropwise at 0 ° C. The reaction was stirred for 30 minutes, then water (1 mL), 10% NaOH (2 mL) and water (3 mL) were added sequentially. The mixture was filtered, concentrated and purified by column chromatography (PE / EtOAc = 2: 1) to give (5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methanol Int. 1-1 was obtained. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 4.58 (d, J = 5.0 Hz, 2H), 2.86 (t, J = 10.8 Hz, 1H), 2.22-2.18 (m, 2H), 2.08-1.79 (m , 7H), 1.58-1.56 (m, 1H), 1.15-1.11 (m, 2H), 1.07-1.03 (m, 2H). LCMS (ESI): m / z 258.2 (M + H) ⁺ .

中間体Ｉｎｔ−１−１（ステップ１からステップ４）について記載されているのと同様に、スピロ［２．５］オクタン−６−カルバルデヒドから出発して、合成により、（５−シクロプロピル−３−（スピロ［２．５］オクタン−６−イル）イソオキサゾール−４−イル）メタノールＩｎｔ−１−２を得た。¹H-NMR (500 MHz, CDCl₃): δ 4.96 (t, J = 5.5 Hz, 1H), 4.35 (d, J = 5.0 Hz, 2H), 2.76-2.71 (m, 1H), 2.17-2.14 (m, 1H), 1.89-1.86 (m, 2H), 1.80-1.74 (m, 2H), 1.63-1.55 (m, 2H), 1.03-0.91 (m, 6H), 0.31-0.28 (m, 2H), 0.22-0.20 (m, 2H).ＬＣＭＳ（ＥＳＩ）：ｍ／ｚ２４８．３（Ｍ＋Ｈ）^＋。 Intermediate Int-1-2: (5-Cyclopropyl-3- (spiro [2.5] octane-6-yl) isoxazol-4-yl) methanol

As described for the intermediate Int-1-1 (step 1 to step 4), starting from spiro [2.5] octane-6-carbaldehyde, the synthesis gives (5-cyclopropyl- 3- (Spiro [2.5] octane-6-yl) isoxazol-4-yl) methanol Int-1-2 was obtained. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 4.96 (t, J = 5.5 Hz, 1H), 4.35 (d, J = 5.0 Hz, 2H), 2.76-2.71 (m, 1H), 2.17-2.14 ( m, 1H), 1.89-1.86 (m, 2H), 1.80-1.74 (m, 2H), 1.63-1.55 (m, 2H), 1.03-0.91 (m, 6H), 0.31-0.28 (m, 2H), 0.22-0.20 (m, 2H). LCMS (ESI): m / z 248.3 (M + H) ^<+> .

中間体Ｉｎｔ−１−３をＷＯ２０１２／０８７５１９に記載されている通り合成した。 Intermediate Int-1-3: (5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methanol

Intermediate Int-1-3 was synthesized as described in WO2012 / 087519.

中間体Ｉｎｔ−１−４をＷＯ２０１２／０８７５１９に記載されている通り合成した。 Intermediate Int-1-4: (5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazol-4-yl) methanol

Intermediate Int-1-4 was synthesized as described in WO2012 / 087519.

中間体Ｉｎｔ−１−５をＷＯ２０１２／０８７５１９に記載されている通り合成した。 Intermediate Int-1-5: (5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazol-4-yl) methanol

The intermediate Int-1-5 was synthesized as described in WO2012 / 087519.

中間体Ｉｎｔ−１−６をＷＯ２００９／０１２１２５に記載されている通り合成した。 Intermediate Int-1-6: (4-Cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methanol

The intermediate Int-1-6 was synthesized as described in WO2009 / 012125.

中間体Ｉｎｔ−１−７をＷＯ２０１２／０８７５１９に記載されている通り合成した。 Intermediate Int-1-7: (5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methanol

The intermediate Int-1-7 was synthesized as described in WO2012 / 087519.

中間体Ｉｎｔ−１−１（ステップ１からステップ４）について記載されているのと同様に、２−（ジフルオロメチル）ベンズアルデヒドから出発して、中間体（５−シクロプロピル−３−（２−（ジフルオロメチル）フェニル）イソオキサゾール−４−イル）メタノールＩｎｔ−１−８を合成した。¹H-NMR (500 MHz, DMSO-d₆): δ 7.81-7.80 (m, 1H), 7.71-7.66 (m, 3H), 6.95 (t, J = 55 Hz, 1H), 5.10 (t, J = 5.0 Hz, 1H), 4.27 (d, J = 5.0 Hz, 2H), 2.33-2.30 (m, 1H), 1.15-1.07 (m, 4H).ＬＣＭＳ（ＥＳＩ）：ｍ／ｚ２６６．２（Ｍ＋Ｈ）^＋。 Intermediate Int-1-8: (5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazol-4-yl) methanol

Starting with 2- (difluoromethyl) benzaldehyde, the intermediate (5-cyclopropyl-3- (2- (2- (2)) is described as described for intermediate Int-1-1 (step 1 to step 4). Difluoromethyl) phenyl) isoxazol-4-yl) methanol Int-1-8 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 7.81-7.80 (m, 1H), 7.71-7.66 (m, 3H), 6.95 (t, J = 55 Hz, 1H), 5.10 (t, J = 5.0 Hz, 1H), 4.27 (d, J = 5.0 Hz, 2H), 2.33-2.30 (m, 1H), 1.15-1.07 (m, 4H). LCMS (ESI): m / z 266.2 (M + H) ⁺ .

中間体（４−シクロプロピル−１−（２，６−ジクロロフェニル）−１Ｈ−ピラゾール−５−イル）メタノールについてＷＯ２００９／０１２１２５に記載されているのと同様に、（２−（ジフルオロメトキシ）フェニル）ヒドラジンから出発して、中間体（４−シクロプロピル−１−（２−（ジフルオロメトキシ）フェニル）−１Ｈ−ピラゾール−５−イル）メタノールＩｎｔ−１−９を合成した。 Intermediate Int-1-9: (4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazol-5-yl) methanol

The intermediate (4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methanol is similar to that described in WO2009 / 012125 (2- (difluoromethoxy) phenyl) Starting from hydrazine, the intermediate (4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazol-5-yl) methanol Int-1-9 was synthesized.

ステップ１：２，６−ジメチル安息香酸から出発して、中間体メチル２，６−ビス（ジフルオロ−メチル）ベンゾエートＩｎｔ−１ａ−１０をＷＯ２００７／１４４３２７に記載の通り調製した。 Intermediate Int-1-10: (3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropylisoxazol-4-yl) methanol

Step 1: Starting from 2,6-dimethylbenzoic acid, the intermediate methyl 2,6-bis (difluoro-methyl) benzoate Int-1a-10 was prepared as described in WO2007 / 144327.

Step 2: To a solution of 2,6-bis (difluoromethyl) benzoate Int-1a-10 (51.3 g, 217 mmol) in THF (550 mL) was added LiAlH ₄ (1N, 430 mL) at 0 ° C. Stir at temperature for 1 h and quench with water (16 mL), 1 N NaOH (32 mL) and then water (48 mL). The mixture was filtered and the crude filtrate was concentrated to give (2,6-bis (difluoromethyl) phenyl) methanol, which was used in the next step without purification.

  Step 3: A solution of (2,6-bis (difluoromethyl) phenyl) methanol (46.2 g, crude) and IBX (189 g, 666 mmol) in acetone (450 mL) was stirred at 50 ° C. overnight, filtered and the filtrate Was evaporated to give 2,6-bis (difluoromethyl) benzaldehyde Int-1b-10, which was used in the next step without purification.

Step 4: Starting from 2,6-bis (difluoromethyl) benzaldehyde Int-1b-10 as described for intermediate Int-1-1 (step 1 to step 4), intermediate ( 3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropylisoxazol-4-yl) methanol Int-1-10 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 7.97 (d, J = 8.0 Hz, 2H), 7.88 (t, J = 8.0 Hz, 1H), 6.69 (t, J = 54.5 Hz, 2H) , 5.02 (t, J = 5.0 Hz, 1H), 4.16 (d, J = 5.0 Hz, 2H), 2.33-2.30 (m, 1H), 1.17-1.10 (m, 4H). LC / MS (ESI): m / z 316.1 (M + H) ^<+> .

Intermediate Int-1-11: 5-Cyclopropyl-3- (2,6-dichlorophenethyl) -4- (hydroxymethyl) oxazol-2 (3H) -one

Step 1: To a solution of methyl 2-isocyanoacetate (72.7 g, 729 mmol) and DBU (111 g, 729 mmol) in THF (1 L), cyclopropanecarboxylic anhydride (112 g, 729 mmol) in THF (100 mL). Was added in portions at 5 ° C. The mixture was stirred at room temperature overnight, concentrated and purified by flash chromatography (PE / EtOAc = 5: 1) to give methyl 5-cyclopropyloxazole-4-carboxylate Int-1a-11. ¹ H-NMR (CDCl ₃ , 300 MHz): δ 1.04-1.18 (m, 4H), 2.74-2.79 (m, 1H), 3.91 (s, 3H), 7.60 (s, 1H).

Step 2: A solution of methyl 5-cyclopropyloxazole-4-carboxylate Int-1a-11 (36.4 g, 218 mmol) and TsOH.H ₂ O (82.9 g, 436 mmol) in MeOH (600 mL) until reflux overnight. Heated. The mixture was cooled to room temperature and concentrated in vacuo. The residue was triturated with Et ₂ O and filtered to give crude methyl 2-amino-3-cyclopropyl-3-oxopropanoate (62.8 g, 191 mmol), which was dissolved in THF (1 .5L) and TEA (77.2 g, 764 mmol). Triphosgene (19.9 g, 67 mmol) was then added to the mixture at −50 ° C. over 1 hour. The solution was diluted with Et ₂ O (500 mL) and NH ₄ Cl saturated aqueous solution (300 mL) was added. The aqueous phase was separated and extracted with Et ₂ O (3 × 1 L). The combined organic extracts were washed with brine (500 mL), dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography (PE / EtOAc = 5: 1) to give methyl 5-cyclopropyl-2- Oxo-2,3-dihydrooxazole-4-carboxylate Int-1b-11 was generated. ¹ H-NMR (CDCl ₃ , 300 MHz): δ 0.99-1.11 (m, 4H), 2.41-2.50 (m, 1H), 3.84 (s, 3H), 8.57 (s, 1H).

Step 3: To a solution of 2- (2,6-dichlorophenyl) ethanol (37.3 g, 195 mmol) and TEA (32.7 g, 235 mmol) in DCM (700 mL) was added MsCl (26.9 g, 235 mmol) at 0 ° C. Added dropwise. After the addition, the solution was stirred at room temperature overnight, diluted with water (200 mL) and extracted with DCM (3 × 400 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography (PE / EtOAc = 5: 1) to give 2,6-dichlorophenethyl methanesulfonate Int-1c-11. Was generated. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 2.95 (s, 3H), 3.43 (t, J = 7.5 Hz, 2H), 4.41 (t, J = 7.5 Hz, 2H), 7.12-7.17 (m, 1H), 7.31 (d, J = 8.4 Hz, 2H).

Step 4: To a solution of methyl 5-cyclopropyl-2-oxo-2,3-dihydrooxazole-4-carboxylate Int-1b-11 (23.5 g, 129 mmol) in DMF (800 mL) was added NaH (5. 7 g, 142 mmol; 60% in mineral oil) was added at 0 ° C. under nitrogen. The mixture was stirred for 15 minutes, then a solution of 2,6-dichlorophenethyl methanesulfonate Int-1c-11 (41.5 g, 154 mmol) in DMF (400 mL) was added dropwise at 0 ° C. After the addition, the mixture was stirred at 100 ° C. overnight, cooled, diluted with water (1500 mL) and extracted with EtOAc (3 × 700 mL). The combined organic layers were washed with water (2 × 200 mL) and brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was washed with PE / EtOAc (5: 1) and methyl 5-cyclopropyl-3- (2,6-dichlorophenethyl) -2-oxo-2,3-dihydrooxazole-4-carboxylate Int-1d -11 was produced. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.97-1.08 (m, 4H), 2.44-2.49 (m, 1H), 3.31 (t, J = 4.8 Hz, 2H). 3.73 (s, 3H), 4.26 (t, J = 4.8 Hz, 2H), 7.08-7.12 (m, 1H), 7.26-7.28 (m, 2H).

Step 5: Methyl 5-cyclopropyl-3- (2,6-dichlorophenethyl) -2-oxo-2,3-dihydro-oxazole-4-carboxylate Int-1d-11 (13. To a solution of 9 g, 39 mmol) was added a solution of LiAlH ₄ in THF (16.3 mL, 39 mmol) at 0 ° C. under nitrogen. After the addition, the solution was stirred at 0 ° C. for 30 min, diluted sequentially with H ₂ O (2 mL), 1M NaOH (2 mL) and H ₂ O (6 mL), filtered and concentrated in vacuo. The residue was washed with PE / EtOAc (2: 1) to give 5-cyclopropyl-3- (2,6-dichlorophenethyl) -4- (hydroxymethyl) oxazol-2 (3H) -one Int-1- 11 was produced. ¹ H-NMR (CD ₃ OD, 300 MHz): δ 0.73-0.77 (m, 2H), 0.83-0.88 (m, 2H), 1.75-1.79 (m, 1H), 3.30-3.38 (m, 2H), 3.95 (t, J = 6.6 Hz, 2H). 4.10 (s, 2H), 7.20-7.25 (m, 1H), 7.37 (d, J = 8.1 Hz, 2H), hydroxyl protons are not resolved. LC / MS (ESI): m / z 328.0 (M + H) ^<+> .

Intermediate Int-1-12: (5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) isoxazol-4-yl) methanol

Step 1: To a solution of 2- (tert-butoxy) acetaldehyde oxime (24.1 g, 184 mmol; prepared as described in WO2009 / 005998) in DMF (600 mL) was added NCS (23.7 g, 184 mmol) at 0 ° C. Added. The mixture was stirred for 1 h, poured into Et ₂ O (800 mL) and washed with brine (450 mL). The organic layer was dried over MgSO ₄ and concentrated to give crude 2- (tert-butoxy) -N-hydroxyacetimidoyl chloride Int-1a-12, which was used as such in the next step.

Step 2: To a solution of ethyl 3-cyclopropyl-3-oxopropanoate (31.6 g, 203 mmol) in THF (600 mL) was added NaOCH ₃ solution in MeOH (0.5 M, 10.9 g, 203 mmol). Added at 0 ° C. After stirring for 5 minutes, a solution of 2- (tert-butoxy) -N-hydroxyacetimidoyl chloride Int-1a-12 (27.9 g, 169 mmol) in THF (200 mL) was added dropwise. The mixture was allowed to warm to room temperature, stirred overnight, poured into Et ₂ O (800 mL), washed with brine (450 mL), concentrated, and crude ethyl 3- (tert-butoxymethyl) -5-cyclo Propyl isoxazole-4-carboxylate Int-1b-12 was obtained and used as such in the next step.

Step 3: To a solution of ethyl 3- (tert-butoxymethyl) -5-cyclopropylisoxazole-4-carboxylate Int-1b-12 (38.4 g, 144 mmol) in DCM (600 mL) was added TFA (100 mL). Added at room temperature. The mixture was stirred at room temperature for 2 hours, concentrated and adjusted to basic pH with aqueous NaHCO ₃ solution. The mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (400 mL), dried over MgSO ₄ , concentrated, purified by column chromatography (PE / EtOAc = 10: 1), and ethyl 5-cyclopropyl-3- (hydroxymethyl). ) Gave isoxazole-4-carboxylate Int-1c-12. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 4.64 (s, 2H), 4.26 (q, J = 7.2 Hz, 2H), 2.79-2.70 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.23-1.13 (m, 4H).

Step 4: Ethyl 5-cyclopropyl-3- (hydroxymethyl) isoxazole-4-carboxylate Int-1c-12 (16.1 g, 76.3 mmol) in toluene (500 mL), 2,6-dimethylphenol ( To a solution of 9.3 g, 76.3 mmol) and PPh ₃ (20 g, 76.3 mmol), DIAD (15.4 g, 76.3 mmol) was added at 0 ° C. The mixture was stirred at 90 ° C. for 2 hours, cooled, concentrated and purified by column chromatography (PE / EtOAc = 15: 1) to give ethyl 5-cyclopropyl-3-((2,6-dimethylphenoxy). ) Methyl) isoxazole-4-carboxylate Int-1d-12. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 7.03 (d, J = 7.8, Hz, 2H), 6.96-6.87 (m, 1H), 5.03 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 2.82-2.76 (m, 1H), 2.18 (s, 6H), 2.14 (s, 3H), 1.28-1.17 (m, 4H).

Step 5: Ethyl 5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) isoxazole-4-carboxylate in a solution of LiAlH ₄ (2.9 g, 77.6 mmol) in THF (250 mL). Int-1d-12 (16.3 g, 51.7 mmol) was added at 0 ° C. The mixture was stirred at room temperature for 1 hour, diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO ₄ , concentrated, purified by column chromatography (PE / EtOAc = 8: 1) and (5-cyclopropyl-3-((2 , 6-Dimethylphenoxy) methyl) isoxazol-4-yl) methanol Int-1-12. ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 7.04 (d, J = 7.5, Hz, 2H), 6.97-6.92 (m, 1H), 5.07 (br s, 1H), 4.85 (s, 2H ), 4.46 (s, 2H), 2.30-2.26 (m, 1H), 2.22 (s, 6H), 1.10-0.96 (m, 4H). LC / MS (ESI): m / z 256.1 (MH ₂ O + H) ⁺

中間体Ｉｎｔ−１−１３をＷＯ２０１１／０２０６１５に記載されている通り合成した。 Intermediate Int-1-13: 2- (3- (2,6-dichlorophenyl) -4- (hydroxymethyl) isoxazol-5-yl) propan-2-ol

The intermediate Int-1-13 was synthesized as described in WO2011 / 020615.

ＤＣＭ（５ｍＬ）中の（５−シクロプロピル−３−（４，４−ジフルオロシクロヘキシル）イソオキサゾール−４−イル）メタノールＩｎｔ−１−１（５００ｍｇ、１．９ｍｍｏｌ）の溶液に、塩化チオニル（４５０ｍｇ、３．８ｍｍｏｌ）を添加した。反応物を室温で１時間にわたって撹拌し、濃縮して、４−（クロロメチル）−５−シクロプロピル−３−（４，４−ジフルオロ−シクロヘキシル）イソオキサゾールＩｎｔ−２−１を生じさせ、これをさらに精製することなく使用した。 Intermediate Int-2-1: 4- (chloromethyl) -5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazole

To a solution of (5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methanol Int-1-1 (500 mg, 1.9 mmol) in DCM (5 mL) was added thionyl chloride (450 mg 3.8 mmol) was added. The reaction was stirred at room temperature for 1 hour and concentrated to give 4- (chloromethyl) -5-cyclopropyl-3- (4,4-difluoro-cyclohexyl) isoxazole Int-2-1, which was Was used without further purification.

中間体Ｉｎｔ−２−１について記載されているのと同様に、（５−シクロプロピル−３−（スピロ［２．５］オクタン−６−イル）イソオキサゾール−４−イル）メタノールＩｎｔ−１−２から出発して、合成により、４−（クロロメチル）−５−シクロプロピル−３−（スピロ［２．５］オクタン−６−イル）イソオキサゾールＩｎｔ−２−２を得た。 Intermediate Int-2-2: 4- (chloromethyl) -5-cyclopropyl-3- (spiro [2.5] octane-6-yl) isoxazole

(5-Cyclopropyl-3- (spiro [2.5] octan-6-yl) isoxazol-4-yl) methanol Int-1-, as described for the intermediate Int-2-1 Starting from 2, the synthesis gave 4- (chloromethyl) -5-cyclopropyl-3- (spiro [2.5] octan-6-yl) isoxazole Int-2-2.

中間体Ｉｎｔ−２−３をＷＯ２０１１／０２０６１５に記載されている通り合成した。 Intermediate Int-2-3: 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole

The intermediate Int-2-3 was synthesized as described in WO2011 / 020615.

中間体Ｉｎｔ−２−１について記載されているのと同様に、（５−シクロプロピル−３−（２−（ジフルオロ−メトキシ）フェニル）イソオキサゾール−４−イル）メタノールＩｎｔ−１−３から出発して、合成により、４−（クロロメチル）−５−シクロプロピル−３−（２−（ジフルオロメトキシ）フェニル）イソオキサゾールＩｎｔ−２−４を得た。 Intermediate Int-2-4: 4- (chloromethyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole

Starting from (5-cyclopropyl-3- (2- (difluoro-methoxy) phenyl) isoxazol-4-yl) methanol Int-1-3 as described for the intermediate Int-2-1 Thus, 4- (chloromethyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole Int-2-4 was obtained by synthesis.

中間体Ｉｎｔ−２−１について記載されているのと同様に、（５−シクロプロピル−３−（２−シクロプロピル−フェニル）イソオキサゾール−４−イル）メタノールＩｎｔ−１−４から出発して、合成により、４−（クロロメチル）−５−シクロプロピル−３−（２−シクロプロピルフェニル）イソオキサゾールＩｎｔ−２−５を得た。 Intermediate Int-2-5: 4- (chloromethyl) -5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazole

Starting from (5-cyclopropyl-3- (2-cyclopropyl-phenyl) isoxazol-4-yl) methanol Int-1-4 as described for the intermediate Int-2-1 By synthesis, 4- (chloromethyl) -5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazole Int-2-5 was obtained.

中間体Ｉｎｔ−２−１について記載されているのと同様に、（５−シクロプロピル−３−（２，６−ジメチル−フェニル）イソオキサゾール−４−イル）メタノールＩｎｔ−１−５から出発して、合成により、４−（クロロメチル）−５−シクロプロピル−３−（２，６−ジメチルフェニル）イソオキサゾールＩｎｔ−２−６を得た。 Intermediate Int-2-6: 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazole

Starting from (5-cyclopropyl-3- (2,6-dimethyl-phenyl) isoxazol-4-yl) methanol Int-1-5 as described for the intermediate Int-2-1. Thus, 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazole Int-2-6 was obtained by synthesis.

中間体Ｉｎｔ−２−１について記載されているのと同様に、（４−シクロプロピル−１−（２，６−ジクロロフェニル）−１Ｈ−ピラゾール−５−イル）メタノールＩｎｔ−１−６から出発して、合成により、５−（クロロメチル）−４−シクロプロピル−１−（２，６−ジクロロフェニル）−１Ｈ−ピラゾールＩｎｔ−２−７を得た。 Intermediate Int-2-7: 5- (chloromethyl) -4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazole

Starting from (4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methanol Int-1-6 as described for the intermediate Int-2-1 Thus, 5- (chloromethyl) -4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazole Int-2-7 was obtained by synthesis.

中間体Ｉｎｔ−２−１について記載されているのと同様に、（５−シクロプロピル−３−（２−（トリフルオロ−メトキシ）フェニル）イソオキサゾール−４−イル）メタノールＩｎｔ−１−７から出発して、合成により、４−（クロロメチル）−５−シクロプロピル−３−（２−（トリフルオロメトキシ）フェニル）イソオキサゾールＩｎｔ−２−８を得た。 Intermediate Int-2-8: 4- (Chloromethyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole

From (5-cyclopropyl-3- (2- (trifluoro-methoxy) phenyl) isoxazol-4-yl) methanol Int-1-7 as described for the intermediate Int-2-1 Starting, the synthesis gave 4- (chloromethyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole Int-2-8.

中間体Ｉｎｔ−２−１について記載されているのと同様に、（５−シクロプロピル−３−（２−（ジフルオロ−メチル）フェニル）イソオキサゾール−４−イル）メタノールＩｎｔ−１−８から出発して、合成により、４−（クロロメチル）−５−シクロプロピル−３−（２−（ジフルオロメチル）フェニル）イソオキサゾールＩｎｔ−２−９を得た。 Intermediate Int-2-9: 4- (chloromethyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole

Starting from (5-cyclopropyl-3- (2- (difluoro-methyl) phenyl) isoxazol-4-yl) methanol Int-1-8 as described for the intermediate Int-2-1 Thus, 4- (chloromethyl) -5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazole Int-2-9 was obtained by synthesis.

中間体Ｉｎｔ−２−１０をＷＯ２０１２／０８７５１９に記載されている通り合成した。 Intermediate Int-2-10: 4- (chloromethyl) -5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazole

The intermediate Int-2-10 was synthesized as described in WO2012 / 087519.

中間体Ｉｎｔ−２−１について記載されているのと同様に、（４−シクロプロピル−１−（２−（ジフルオロメトキシ）フェニル）−１Ｈ−ピラゾール−５−イル）メタノールＩｎｔ−１−９から出発して、合成により、５−（クロロ−メチル）−４−シクロプロピル−１−（２−（ジフルオロメトキシ）フェニル）−１Ｈ−ピラゾールＩｎｔ−２−１１を得た。 Intermediate Int-2-11: 5- (chloromethyl) -4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazole

From (4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazol-5-yl) methanol Int-1-9 as described for the intermediate Int-2-1 Starting, the synthesis gave 5- (chloro-methyl) -4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazole Int-2-11.

中間体Ｉｎｔ−２−１について記載されているのと同様に、（３−（２，６−ビス（ジフルオロメチル）フェニル）−５−シクロプロピルイソオキサゾール−４−イル）メタノールＩｎｔ−１−１０から出発して、合成により、３−（２，６−ビス（ジフルオロ−メチル）フェニル）−４−（クロロメチル）−５−シクロプロピルイソオキサゾールＩｎｔ−２−１２を得た。 Intermediate Int-2-12: 3- (2,6-bis (difluoromethyl) phenyl) -4- (chloromethyl) -5-cyclopropylisoxazole

(3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropylisoxazol-4-yl) methanol Int-1-10 as described for the intermediate Int-2-1 Starting from, the synthesis gave 3- (2,6-bis (difluoro-methyl) phenyl) -4- (chloromethyl) -5-cyclopropylisoxazole Int-2-12.

ＣＨ_２Ｃｌ_２（１００ｍＬ）中の（３−（２，６−ジクロロフェニル）−５−メチルイソオキサゾール−４−イル）メタノール（５．０ｇ、１７．６ｍｍｏｌ）の溶液に、ＣＢｒ_４（８．７ｇ、２６．４ｍｍｏｌ）およびＰＰｈ_３（７．０ｇ、２６．４ｍｍｏｌ）を室温で添加した。混合物を２時間にわたって撹拌し、濃縮し、フラッシュクロマトグラフィーによって精製して、４−（ブロモメチル）−３−（２，６−ジクロロフェニル）−５−メチルイソオキサゾールＩｎｔ−２−１３を得た。 Intermediate Int-2-13: 4- (Bromomethyl) -3- (2,6-dichlorophenyl) -5-methylisoxazole

To a solution of (3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methanol (5.0 g, 17.6 mmol) in CH ₂ Cl ₂ (100 mL) was added CBr ₄ (8.7 g , 26.4 mmol) and PPh ₃ (7.0 g, 26.4 mmol) were added at room temperature. The mixture was stirred for 2 hours, concentrated and purified by flash chromatography to give 4- (bromomethyl) -3- (2,6-dichlorophenyl) -5-methylisoxazole Int-2-13.

中間体Ｉｎｔ−２−１３について記載されているのと同様に、（３−（２，６−ジクロロフェニル）−５−イソプロピル−イソオキサゾール−４−イル）メタノールから出発して、合成により、４−（ブロモメチル）−３−（２，６−ジクロロフェニル）−５−イソプロピルイソオキサゾールＩｎｔ−２−１４を得た。 Intermediate Int-2-14: 4- (Bromomethyl) -3- (2,6-dichlorophenyl) -5-isopropylisoxazole

As described for the intermediate Int-2-13, starting from (3- (2,6-dichlorophenyl) -5-isopropyl-isoxazol-4-yl) methanol, the synthesis gives 4- (Bromomethyl) -3- (2,6-dichlorophenyl) -5-isopropylisoxazole Int-2-14 was obtained.

ＤＣＭ（１２０ｍＬ）中の２−（３−（２，６−ジクロロフェニル）−４−（ヒドロキシメチル）イソオキサゾール−５−イル）プロパン−２−オールＩｎｔ−１−１３（６．８ｇ、２２６ｍｍｏｌ）の溶液に、ＳＯＣｌ_２（１７．２ｍＬ、２３７ｍｍｏｌ）を０℃で添加した。混合物を室温で１５分間にわたって撹拌し、ＮａＣＯ_３飽和水溶液でクエンチし、ＥｔＯＡｃ（３×１５０ｍＬ）で抽出した。合わせた有機層をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、カラムクロマトグラフィー（ＰＥ／ＥｔＯＡｃ＝３０：１）によって精製して、２−（４−（クロロメチル）−３−（２，６−ジクロロフェニル）イソオキサゾール−５−イル）プロパン−２−オールＩｎｔ−２−１５を生じさせた。¹H-NMR (CDCl₃, 300 MHz): δ 7.47-7.37 (m, 3H), 4.51 (s, 2H), 2.43 (s, 1H), 1.75 (s, 6H). Intermediate Int-2-15: 2- (4- (Chloromethyl) -3- (2,6-dichlorophenyl) isoxazol-5-yl) propan-2-ol

Of 2- (3- (2,6-dichlorophenyl) -4- (hydroxymethyl) isoxazol-5-yl) propan-2-ol Int-1-13 (6.8 g, 226 mmol) in DCM (120 mL) To the solution was added SOCl ₂ (17.2 mL, 237 mmol) at 0 ° C. The mixture was stirred at room temperature for 15 minutes, quenched with saturated aqueous NaCO ₃ and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (PE / EtOAc = 30: 1) to give 2- (4- (chloromethyl) -3- This gave (2,6-dichlorophenyl) isoxazol-5-yl) propan-2-ol Int-2-15. ¹ H-NMR (CDCl ₃ , 300 MHz): δ 7.47-7.37 (m, 3H), 4.51 (s, 2H), 2.43 (s, 1H), 1.75 (s, 6H).

ＤＣＭ（８０ｍＬ）中の２−（４−（クロロメチル）−３−（２，６−ジクロロフェニル）イソオキサゾール−５−イル）プロパン−２−オールＩｎｔ−２−１５（２．８０ｇ、９．１ｍｍｏｌ）の溶液に、ＤＡＳＴ（１．５ｍＬ、１１．４ｍｍｏｌ）を添加した。混合物を０℃で１．５時間にわたって撹拌し、ＮａＨＣＯ_３飽和水溶液でクエンチし、ＥｔＯＡｃ（３×１００ｍＬ）で抽出した。合わせた有機層をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮し、カラムクロマトグラフィー（ＰＥ／ＥｔＯＡｃ＝３０：１）によって精製して、４−（クロロメチル）−３−（２，６−ジクロロ−フェニル）−５−（２−フルオロプロパン−２−イル）イソオキサゾールＩｎｔ−２−１６を生じさせた。¹H-NMR (CDCl₃, 300 MHz): δ 7.47-7.37 (m, 3H), 4.43 (s, 2H), 1.87 (d, J = 22.2 Hz, 6H).ＬＣＭＳ（ＥＳＩ）：ｍ／ｚ３２１．９（Ｍ＋１）^＋。 Intermediate Int-2-16: 4- (chloromethyl) -3- (2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) isoxazole

2- (4- (Chloromethyl) -3- (2,6-dichlorophenyl) isoxazol-5-yl) propan-2-ol Int-2-15 (2.80 g, 9.1 mmol) in DCM (80 mL) DAST (1.5 mL, 11.4 mmol) was added to the solution. The mixture was stirred at 0 ° C. for 1.5 h, quenched with saturated aqueous NaHCO ₃ and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by column chromatography (PE / EtOAc = 30: 1) to give 4- (chloromethyl) -3- (2, 6-Dichloro-phenyl) -5- (2-fluoropropan-2-yl) isoxazole Int-2-16 was generated. ¹ H-NMR (CDCl ₃ , 300 MHz): δ 7.47-7.37 (m, 3H), 4.43 (s, 2H), 1.87 (d, J = 22.2 Hz, 6H). LCMS (ESI): m / z 321. 9 (M + 1) ⁺ .

中間体Ｉｎｔ−２−１について記載されているのと同様に、（５−シクロプロピル−３−（（２，６−ジメチル−フェノキシ）メチル）イソオキサゾール−４−イル）メタノールＩｎｔ−１−１２から出発して、合成により、４−（クロロメチル）−５−シクロプロピル−３−（（２，６−ジメチルフェノキシ）メチル）イソオキサゾールＩｎｔ−２−１７を得た。 Intermediate Int-2-17: 4- (chloromethyl) -5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) isoxazole

(5-Cyclopropyl-3-((2,6-dimethyl-phenoxy) methyl) isoxazol-4-yl) methanol Int-1-12 as described for the intermediate Int-2-1 Starting from, the synthesis gave 4- (chloromethyl) -5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) isoxazole Int-2-17.

ＣＨ_２Ｃｌ_２（５ｍＬ）中の（４−シクロプロピル−１−（２，６−ジクロロフェニル）−１Ｈ−ピラゾール−５−イル）メタノールＩｎｔ−１−６（２８３ｍｇ、１．０ｍｍｏｌ）の溶液に、ＣＢｒ_４（４９７ｍｇ、１．５ｍｍｏｌ）およびＰＰｈ_３（３９３ｍｇ、１．５ｍｍｏｌ）を室温で添加した。混合物を室温で２時間にわたって撹拌し、濃縮し、シリカゲルでのフラッシュクロマトグラフィーによって精製して、５−（ブロモメチル）−４−シクロプロピル−１−（２，６−ジクロロフェニル）−１Ｈ−ピラゾールＩｎｔ−２−１８を得た。 Intermediate Int-2-18: 5- (Bromomethyl) -4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazole

To a solution of (4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methanol Int-1-6 (283 mg, 1.0 mmol) in CH ₂ Cl ₂ (5 mL), CBr ₄ (497 mg, 1.5 mmol) and PPh ₃ (393 mg, 1.5 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours, concentrated and purified by flash chromatography on silica gel to give 5- (bromomethyl) -4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazole Int— 2-18 was obtained.

乾燥ＤＭＦ中のＮａＨ（油中６０％；２．０当量）の０℃の懸濁液に、ヒドロキシ−アセタール誘導体（１．２当量）を添加した。混合物を０℃で３０分間にわたって撹拌し、次いで、ＤＭＦ（５ｍＬ）中のハロメチル−Ｚ（１．０当量）の混合物を添加した。混合物を室温に加温し、１時間にわたって撹拌し、水で慎重に希釈し、ＥｔＯＡｃで抽出した。合わせた有機層をブラインで洗浄し、乾燥させ、濾過し、濃縮し、残留物をＴＬＣまたはフラッシュクロマトグラフィーによって精製して、選択した中間体Ｉｎｔ−３を生じさせた。 General Procedure A for Synthesis of Intermediate Int-3

To a 0 ° C. suspension of NaH (60% in oil; 2.0 eq) in dry DMF was added hydroxy-acetal derivative (1.2 eq). The mixture was stirred at 0 ° C. for 30 minutes, then a mixture of halomethyl-Z (1.0 eq) in DMF (5 mL) was added. The mixture was warmed to room temperature, stirred for 1 hour, carefully diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated, and the residue was purified by TLC or flash chromatography to yield the selected intermediate Int-3.

乾燥ＴＨＦ（１０容量）中のＮａＨ（鉱油中６０％、１．３当量）の懸濁液に、乾燥ＴＨＦ（３容量）中のスピロ［ビシクロ［３．２．１］オクタン−８，２’−［１，３］ジオキソラン］−３−オールＩｎｔ−５−２（１．０当量）を０℃で添加した。反応混合物を０℃で１．５時間にわたって撹拌し、次いでブロモ−またはクロロメチル−Ｚ（１．２当量）を０℃で添加した。混合物を終夜還流撹拌し、ＮＨ_４Ｃｌ（飽和）でクエンチし、ＥｔＯＡｃで抽出した。有機層を合わせ、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。粗生成物をシリカゲルクロマトグラフィーによって精製して、選択した中間体Ｉｎｔ−３ａ（メジャー異性体）およびＩｎｔ−３−ｂ（マイナー異性体）を得た。マイナー異性体は、単離されないこともある。 Alternative General Procedure A2 for the Synthesis of Intermediate Int-3

To a suspension of NaH (60% in mineral oil, 1.3 eq) in dry THF (10 vol) was added spiro [bicyclo [3.2.1] octane-8,2 ′ in dry THF (3 vol). -[1,3] Dioxolane] -3-ol Int-5-2 (1.0 eq) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.5 hours, then bromo- or chloromethyl-Z (1.2 eq) was added at 0 ° C. The mixture was stirred at reflux overnight, quenched with NH ₄ Cl (saturated) and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel chromatography to give the selected intermediates Int-3a (major isomer) and Int-3-b (minor isomer). Minor isomers may not be isolated.

一般的手順Ａに従って、４−（クロロメチル）−５−シクロプロピル−３−（４，４−ジフルオロシクロヘキシル）イソオキサゾールＩｎｔ−２−１（５２０ｍｇ、１．９ｍｍｏｌ）および１，４−ジオキサスピロ［４．５］デカン−８−オールから出発して、中間体４−（（１，４−ジオキサスピロ［４．５］デカン−８−イルオキシ）メチル）−５−シクロプロピル−３−（４，４−ジフルオロシクロ−ヘキシル）イソオキサゾールＩｎｔ−３−１を合成し、ＴＬＣ（ＰＥ／ＥｔＯＡｃ＝４：１）によって精製した。 Intermediate Int-3-1: 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazole

Following general procedure A, 4- (chloromethyl) -5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazole Int-2-1 (520 mg, 1.9 mmol) and 1,4-dioxaspiro [4 .5] Starting from decan-8-ol, the intermediate 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (4,4- Difluorocyclo-hexyl) isoxazole Int-3-1 was synthesized and purified by TLC (PE / EtOAc = 4: 1).

一般的手順Ａに従って、４−（クロロメチル）−５−シクロプロピル−３−（スピロ［２．５］オクタン−６−イル）イソオキサゾールＩｎｔ−２−２（１９０ｍｇ、１．２ｍｍｏｌ）および１，４−ジオキサスピロ［４．５］デカン−８−オールから出発して、中間体４−（（１，４−ジオキサスピロ［４．５］デカン−８−イルオキシ）メチル）−５−シクロプロピル−３−（スピロ［２．５］オクタン−６−イル）イソオキサゾールＩｎｔ−３−２を合成し、ＴＬＣ（ＰＥ／ＥｔＯＡｃ＝４：１）によって精製した。 Intermediate Int-3-2: 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (spiro [2.5] octane-6-yl ) Isoxazole

According to general procedure A, 4- (chloromethyl) -5-cyclopropyl-3- (spiro [2.5] octane-6-yl) isoxazole Int-2-2 (190 mg, 1.2 mmol) and 1, Starting from 4-dioxaspiro [4.5] decan-8-ol, the intermediate 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (Spiro [2.5] octane-6-yl) isoxazole Int-3-2 was synthesized and purified by TLC (PE / EtOAc = 4: 1).

一般的手順Ａに従って、４−（クロロメチル）−５−シクロプロピル−３−（２，６−ジクロロフェニル）イソオキサゾールＩｎｔ−２−３および９−ヒドロキシ−１，４−ジオキサジスピロ［４．１．３．１］ウンデカンＩｎｔ−５−１から出発して、中間体４−（（１，４−ジオキサジスピロ［４．１．３．１］ウンデカン−９−イルオキシ）メチル）−５−シクロプロピル−３−（２，６−ジクロロ−フェニル）イソオキサゾールＩｎｔ−３−３を合成した。 Intermediate Int-3-3: 4-((1,4-Dioxadispiro [4.1.3.1] undecan-9-yloxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) iso Oxazole

According to general procedure A, 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-2-3 and 9-hydroxy-1,4-dioxadispiro [4.1.3 .1] Starting from undecane Int-5-1, the intermediate 4-((1,4-dioxadispiro [4.1.3.1] undecan-9-yloxy) methyl) -5-cyclopropyl-3- (2,6-Dichloro-phenyl) isoxazole Int-3-3 was synthesized.

一般的手順Ａに従って、４−（クロロメチル）−５−シクロプロピル−３−（２，６−ジクロロフェニル）イソオキサゾールＩｎｔ−２−３および１，４−ジオキサスピロ［４．５］デカン−８−オールから出発して、中間体４−（（１，４−ジオキサスピロ［４．５］デカン−８−イルオキシ）メチル）−５−シクロプロピル−３−（２，６−ジクロロフェニル）イソオキサゾールＩｎｔ−３−４を合成した。 Intermediate Int-3-4: 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole

According to general procedure A 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-2-3 and 1,4-dioxaspiro [4.5] decan-8-ol Starting from the intermediate 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-3- 4 was synthesized.

一般的手順Ａに従って、４−（クロロメチル）−５−シクロプロピル−３−（２−（ジフルオロメトキシ）フェニル）イソオキサゾールＩｎｔ−２−４および１，４−ジオキサスピロ［４．５］デカン−８−オールから出発して、中間体４−（（１，４−ジオキサスピロ［４．５］デカン−８−イルオキシ）メチル）−５−シクロプロピル−３−（２−（ジフルオロメトキシ）フェニル）イソオキサゾールＩｎｔ−３−５を合成した。 Intermediate Int-3-5: 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole

According to general procedure A 4- (chloromethyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole Int-2-4 and 1,4-dioxaspiro [4.5] decane-8 Starting from -ol, the intermediate 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole Int-3-5 was synthesized.

Intermediate Int-3-6: 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazole

Following general procedure A, 4- (chloromethyl) -5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazole Int-2-5 and 1,4-dioxaspiro [4.5] decan-8-ol Starting from the intermediate 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazole Int-3- 6 was synthesized.
Intermediate Int-3-7: 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazole

According to general procedure A 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazole Int-2-6 and 1,4-dioxaspiro [4.5] decane-8- Starting from all, the intermediate 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazole Int- 3-7 was synthesized.
Intermediate Int-3-8: 5-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazole

According to general procedure A, 5- (chloromethyl) -4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazole Int-2-7 and 1,4-dioxaspiro [4.5] decane-8 Starting from -ol, the intermediate 5-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazole Int-3-8 was synthesized.
Intermediate Int-3-9: 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole

According to general procedure A 4- (chloromethyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole Int-2-8 and 1,4-dioxaspiro [4.5] decane- Starting from 8-ol, the intermediate 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) Isoxazole Int-3-9 was synthesized.
Intermediate Int-3-10: 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazole

According to general procedure A, 4- (chloromethyl) -5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazole Int-2-9 and 1,4-dioxaspiro [4.5] decane-8 Starting from the ol, the intermediate 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazole Int-3-10 was synthesized.
Intermediate Int-3-11: 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) Isoxazole

According to general procedure A 4- (chloromethyl) -5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazole Int-2-10 and 1,4-dioxaspiro [4.5] Starting from decan-8-ol, the intermediate 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (3,5-dichloropyridine- 4-yl) isoxazole Int-3-11 was synthesized.
Intermediate Int-3-12: 5-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H- Pyrazole

According to general procedure A, 5- (chloromethyl) -4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazole Int-2-11 and 1,4-dioxaspiro [4.5] decane Starting from -8-ol, the intermediate 5-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazole Int-3-12 was synthesized.
Intermediate Int-3-13: 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropyl Isoxazole

  According to general procedure A 3- (2,6-bis (difluoromethyl) phenyl) -4- (chloromethyl) -5-cyclopropylisoxazole Int-2-12 and 1,4-dioxaspiro [4.5] Starting from decan-8-ol, the intermediate 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -3- (2,6-bis (difluoromethyl) phenyl)- 5-Cyclopropylisoxazole Int-3-13 was synthesized.

Intermediates Int-3-14a and Int-3-14b: 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 3s, 5S) -spiro [bicyclo [3.2. 1] Octane-8,2 ′-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole (Int-3-14a) and 5-cyclopropyl-3- (2,6-dichlorophenyl)- 4-((((1R, 3r, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolan] -3-yl) oxy) methyl) isoxazole (Int -3-14b)

The target intermediate was synthesized as a mixture using 4- (bromomethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole (Intermediate 1a of Example 1) according to General Procedure A2. . The crude product was purified by silica gel chromatography to give isolated 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 3s, 5S) -spiro [bicyclo [3.2. 1) Octane-8,2 ′-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole Int-3-14a and 5-cyclopropyl-3- (2,6-dichlorophenyl) -4- ((((1R, 3r, 5S) -spiro [bicyclo [3.2.1] octane-8,2 '-[1,3] dioxolan] -3-yl) oxy) methyl) isoxazole Int-3- 14b was produced.
Intermediate Int-3-15: 5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) -4-((((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane- 8,2 ′-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole

Following the general procedure A2, using 4- (chloromethyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole Int-2-4, the intermediate 5-cyclopropyl-3- (2- (Difluoromethoxy) phenyl) -4-((((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3- Yl) oxy) methyl) isoxazole (Int-3-15) was synthesized.
Intermediate Int-3-16: 5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) -4-((((1R, 3s, 5S) -spiro [bicyclo [3.2.1 ] Octane-8,2 '-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole

  Following the general procedure A2, using 4- (chloromethyl) -5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazole Int-2-10, the intermediate 5-cyclopropyl -3- (3,5-dichloropyridin-4-yl) -4-((((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 '-[1,3 ] Dioxolane] -3-yl) oxy) methyl) isoxazole (Int-3-16) was synthesized.

Intermediates Int-3-17a and Int-3-17b: 3- (2,6-dichlorophenyl) -5-methyl-4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] Octane-8,2 ′-[1,3] dioxolane] -3-yloxy) methyl) isoxazole (Int-3-17a) and 3- (2,6-dichloro-phenyl) -5-methyl-4- ( ((1R, 3r, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-yloxy) methyl) isoxazole (Int-3-17b)

The target intermediate was synthesized using 4- (bromomethyl) -3- (2,6-dichlorophenyl) -5-methylisoxazole Int-2-13 according to general procedure A2 and purified by silica gel chromatography. Major isomer 3- (2,6-dichlorophenyl) -5-methyl-4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 '-[1 , 3] Dioxolane] -3-yloxy) methyl) isoxazole Int-3-17a and minor isomer 3- (2,6-dichlorophenyl) -5-methyl-4-(((1R, 3r, 5S) -spiro [Bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-yloxy) methyl) isoxazole Int-3-17b was obtained.
Intermediate Int-3-18: 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 5S) -3-methylspiro [bicyclo [3.2.1] octane-8, 2 '-[1,3] Dioxolane] -3-yl) oxy) methyl) isoxazole

According to general procedure A2, (1R, 5S) -3-methylspiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-ol (500 mg, 2.75 mmol) Int The target intermediate was synthesized using -9-1 and 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-2-3 and silica gel chromatography (PE / EtOAc = 10: 1) to give 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 5S) -3-methylspiro [bicyclo [3.2.1] Octane-8,2 ′-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole Int-3-18 was obtained.
Intermediate Int-3-19: 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 5S) -3- (difluoro-methyl) spiro [bicyclo [3.2.1 ] Octane-8,2 '-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole

According to general procedure A2, (1R, 5S) -3- (difluoromethyl) spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-ol Int-9- The target intermediate was synthesized using 2 and 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-2-3 and silica gel chromatography (PE / EtOAc = 10: 1) to give 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 5S) -3- (difluoromethyl) spiro [bicyclo [3.2.1 ] Octane-8,2 ′-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole Int-3-19 was obtained.
Intermediate Int-3-20: 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 5S) -3- (methoxymethyl) spiro [bicyclo [3.2.1] Octane-8,2 ′-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole

According to general procedure A2, (1R, 5S) -3- (methoxymethyl) spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-ol Int-9- The target intermediate was synthesized using 3 and 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-2-3 and silica gel chromatography (PE / EtOAc = 10: 1) to give 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 5S) -3- (methoxymethyl) spiro [bicyclo [3.2.1 ] Octane-8,2 '-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole Int-3-20 was obtained.
Intermediate Int-3-21: 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((3a′R, 6a ′S) -hexahydro-1′H-spiro [[1,3 ] Dioxolane-2,2'-pentalene] -5'-yl) oxy) methyl) isoxazole

According to general procedure A2, (3a′R, 6a ′S) -hexahydro-1′H-spiro [[1,3] dioxolane-2,2′-pentalene] -5′-ol Int-11-1 and 4 The target intermediate was synthesized using-(chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-2-3 and chromatographed on silica gel (PE / EtOAc = 5: 1) ) To give the single isomer 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((3a′R, 6a ′S) -hexahydro-1′H-spiro [[ 1,3] dioxolane-2,2′-pentalene] -5′-yl) oxy) methyl) isoxazole Int-3-21 was obtained.
Intermediate Int-3-22: 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-(((1R, 4R) -spiro [bicyclo [2.2.1] heptane-2,2'- [1,3] Dioxolane] -5-yloxy) methyl) isoxazole

According to general procedure A2, (1R, 4R) -spiro [bicyclo [2.2.1] heptane-2,2 ′-[1,3] dioxolane] -5-ol Int-11-2 and 4- (chloro The target intermediate was synthesized using methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-2-3 and purified by silica gel chromatography (PE / EtOAc = 5: 1) Single isomer 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-(((1R, 4R) -spiro [bicyclo [2.2.1] heptane-2,2'- [1,3] Dioxolane] -5-yloxy) methyl) isoxazole Int-3-22 was obtained.
Intermediate Int-3-23: 5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) -4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane -8,2 '-[1,3] dioxolane] -3-yloxy) methyl) isoxazole

Following the general procedure A2, using 4- (chloromethyl) -5-cyclopropyl-3-((2,6-dimethyl-phenoxy) methyl) isoxazole Int-2-17, the intermediate 5-cyclopropyl -3-((2,6-dimethylphenoxy) methyl) -4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 '-[1,3] dioxolane ] -3-yloxy) methyl) isoxazole (Int-3-23) was synthesized.
Intermediate Int-3-24: 3- (2,6-dichlorophenyl) -5-isopropyl-4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ' -[1,3] dioxolane] -3-yloxy) methyl) isoxazole

Following the general procedure A2, using 4- (bromomethyl) -3- (2,6-dichlorophenyl) -5-isopropylisoxazole Int-2-14, intermediate 3- (2,6-dichlorophenyl) -5 -Isopropyl-4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 '-[1,3] dioxolan] -3-yloxy) methyl) isoxazole (Int -3-24) was synthesized.
Intermediate Int-3-25: 3- (2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) -4-(((1R, 3s, 5S) -spiro [bicyclo [3.2 .1] Octane-8,2 ′-[1,3] dioxolane] -3-yloxy) methyl) isoxazole

Following general procedure A2, using 4- (chloromethyl) -3- (2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) isoxazole Int-2-16, intermediate 3 -(2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) -4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ' -[1,3] Dioxolane] -3-yloxy) methyl) isoxazole (Int-3-25) was synthesized.
Intermediate Int-3-26: 2- (3- (2,6-dichlorophenyl) -4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2'- [1,3] Dioxolane] -3-yloxy) methyl) isoxazol-5-yl) propan-2-ol

Following general procedure A2, using 2- (4- (chloromethyl) -3- (2,6-dichlorophenyl) isoxazol-5-yl) propan-2-ol Int-2-15, intermediate 2 -(3- (2,6-dichlorophenyl) -4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 '-[1,3] dioxolane] -3 -Iyloxy) methyl) isoxazol-5-yl) propan-2-ol (Int-3-26) was synthesized.
Intermediate Int-3-27: 4-Cyclopropyl-1- (2,6-dichlorophenyl) -5-((((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8, 2 '-[1,3] dioxolane] -3-yl) oxy) methyl) -1H-pyrazole

According to general procedure A2, using 5- (bromomethyl) -4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazole Int-2-18, intermediate 4-cyclopropyl-1- ( 2,6-dichlorophenyl) -5-((((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 '-[1,3] dioxolane] -3-yl) oxy ) Methyl) -1H-pyrazole (Int-3-27) was synthesized.
Intermediate Int-3-28: 4-((1,4-Dioxaspiro [4.4] nonan-7-yloxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole

In a dry flask, a solution of 1,4-dioxaspiro [4.4] nonan-7-ol (220 mg, 1.53 mmol) in DMA (10 mL) was sodium hydride (60% dispersion in oil; 61 mg, 1. 53 mmol) and stirred for 40 minutes. A solution of 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole (Int-2-3, 420 mg, 1.39 mmol) in DMA (5 mL) was added and the mixture was Stir at room temperature for 2 hours, quench with water, stir for 15 minutes, then concentrate in vacuo, dilute with EtOAc and water and separate. The organic layer was washed 4 times with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purify by chromatography (ISCO 40 g silica, 0-100% EtOAc / hexanes) to obtain the desired product 4-((1,4-dioxaspiro [4.4] nonan-7-yloxy) methyl) -5-cyclo Propyl-3- (2,6-dichlorophenyl) isoxazole (Int-3-28) was obtained.
Intermediate Int-3-29: 4-(((1R, 5S) -3-oxaspiro [bicyclo [3.3.1] nonane-9,2 '-[1,3] dioxolane] -7-yloxy) methyl ) -5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazole

To a suspension of NaH (60% in mineral oil) (580 mg, 14.4 mmol) in THF (30 mL) was added (1R, 5S) -3-oxaspiro [bicyclo [3.3.1] in THF (10 mL). Nonan-9,2 ′-[1,3] dioxolane] -7-ol Int-5-3 (570 mg, 2.88 mmol) was added at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1.5 hours and then 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-2-3 (1.2 g, 3. 46 mmol) was added at 0 ° C. and stirred at reflux overnight. The reaction was quenched with NH ₄ Cl (saturated) and extracted with EtOAc (3 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over Na ₂ SO ₄ , concentrated and purified by chromatography to give 4-(((1R, 5S) -3-oxaspiro [bicyclo [3 3.1] Nonane-9,2 ′-[1,3] dioxolane] -7-yloxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-3-29 It was.
General Procedure B for the Synthesis of Intermediate Int-4

To a selected ketal Int-3 (1.0 eq) solution in acetone is added aqueous HCl (1 M), the mixture is stirred at room temperature for 2 h, concentrated, and the residue is purified by TLC or flash chromatography. This yielded the intermediate Int-4.
Alternative general procedure B2 for the synthesis of intermediate Int-4

To a stirred solution of the selected cyclic ketal Int-3 (1.0 eq) in acetone / H ₂ O (125 vol, 4: 1, v: v) is added p-TsOH (0.45 eq) at room temperature. Added. The mixture was stirred at reflux for 72 hours. The solvent was concentrated under reduced pressure and the pH of the mixture was adjusted to approximately pH = 8 with aqueous NaHCO ₃ solution. The mixture was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel chromatography.
Intermediate Int-4-1: 4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methoxy) cyclohexanone

According to general procedure B, 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazole Int-3- Intermediate 4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methoxy starting from 1 (600 mg, 1.5 mmol) and aqueous HCl (3 mL, 1M) ) Cyclohexanone Int-4-1 was synthesized and purified by TLC (PE / EtOAc = 3: 1).
Intermediate Int-4-2: 4-((5-cyclopropyl-3- (spiro [2.5] octane-6-yl) isoxazol-4-yl) methoxy) cyclohexanone

According to general procedure B, ((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (spiro [2.5] octane-6-yl) isoxazole Int Starting with -3-2 (230 mg, 0.6 mmol) and aqueous HCl (3 mL, 1 M), intermediate 4-((5-cyclopropyl-3- (spiro [2.5] octane-6-yl) Isoxazol-4-yl) methoxy) cyclohexanone Int-4-2 was synthesized and purified by TLC (PE / EtOAc = 3: 1).
Intermediate Int-4-3: 6-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) spiro [3.3] heptan-2-one

4-((1,4-Dioxadispiro [4.1.3.1] undecan-9-yloxy) methyl) -5-cyclopropyl-3- (in acetone / H ₂ O (1: 1, 50 mL). 2,6-Dichlorophenyl) isoxazole Int-3-3 (500 mg) and p-TsOH (210 mg) instead of aqueous HCl solution according to general procedure B followed by intermediate 6-((5-cyclopropyl -3- (2,6-Dichlorophenyl) isoxazol-4-yl) methoxy) spiro [3.3] heptan-2-one Int-4-3 was synthesized.
Intermediate Int-4-4: 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone

According to general procedure B, 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-3-4 Starting from the intermediate 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 was synthesized.
Intermediate Int-4-5: 4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) cyclohexanone

According to general procedure B, 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole Int-3 Starting from -5, the intermediate 4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-5 was synthesized.
Intermediate Int-4-6: 4-((5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazol-4-yl) methoxy) cyclohexanone

According to general procedure B, 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazole Int-3-6 Starting from the intermediate 4-((5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-6 was synthesized.
Intermediate Int-4-7: 4-((5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazol-4-yl) methoxy) cyclohexanone

According to general procedure B, 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazole Int-3- Starting from 7, the intermediate 4-((5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-7 was synthesized.
Intermediate Int-4-8: 4-((4-Cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) cyclohexanone

According to general procedure B, 5-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazole Int-3 Starting from -8, the intermediate 4-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) cyclohexanone Int-4-8 was synthesized.
Intermediate Int-4-9: 4-((5-Cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) cyclohexanone

Following general procedure B, 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazole Int- The intermediate 4-((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-9 was synthesized starting from 3-9.
Intermediate Int-4-10: 4-((5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazol-4-yl) methoxy) cyclohexanone

According to general procedure B, 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazole Int-3 Starting from -10, the intermediate 4-((5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-10 was synthesized.
Intermediate Int-4-11: 4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) cyclohexanone

According to General Procedure B, 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazole Starting from Int-3-11, the intermediate 4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-11 Was synthesized.
Intermediate Int-4-12: 4-((4-Cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazol-5-yl) methoxy) cyclohexanone

According to general procedure B, 5-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazole Int Starting from -3-12, the intermediate 4-((4-cyclo-propyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazol-5-yl) methoxy) cyclohexanone Int-4-12 Synthesized.
Intermediate Int-4-13: 4-((3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropylisoxazol-4-yl) methoxy) cyclohexanone

According to general procedure B 4-((1,4-dioxaspiro [4.5] decan-8-yloxy) methyl) -3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropylisoxazole Starting from Int-3-13, the intermediate 4-((3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropylisoxazol-4-yl) methoxy) cyclohexanone Int-4-13 Was synthesized.
Intermediate Int-4-14a: (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1 ] Octane-8-on

According to general procedure B2, 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ' Starting from-[1,3] dioxolan] -3-yl) oxy) methyl) isoxazole Int-3-14a intermediate (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-Dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo- [3.2.1] octan-8-one Int-4-14a was synthesized. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.44-7.41 (m, 2H), 7.37-7.33 (m, 1H), 4.29 (s, 2H), 3.85-3.78 (m, 1H), 2.16-2.08 ( m, 5H), 1.97-1.92 (m, 2H), 1.70-1.65 (m, 4H), 1.29-1.24 (m, 2H), 1.15-1.10 (m, 2H). LCMS (ESI): m / z 405. 6 (M + 1) ⁺ .
Intermediate Int-4-14b: (1R, 3r, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1 ] Octane-8-on

According to general procedure B2, 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 3r, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′ Starting from-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole Int-3-14b intermediate (1R, 3r, 5S) -3-((5-cyclopropyl-3- (2,6-Dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-one Int-4-14b was synthesized.
Intermediate Int-4-15: (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) bicyclo [3.2 .1] Octane-8-one

According to general procedure B2, 5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) -4-((((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8, Starting from 2 ′-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole Int-3-15, the intermediate (1R, 3s, 5S) -3-((5-cyclopropyl- 3- (2- (Difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-one Int-4-15 was synthesized.
Intermediate Int-4-16: (1R, 3s, 5S) -3-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) bicyclo [ 3.2.1] Octane-8-on

According to general procedure B2, 5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) -4-((((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane Starting from -8,2 '-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole Int-3-16, the intermediate (1R, 3s, 5S) -3-((5- Cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-one Int-4-16 was synthesized.
Intermediate Int-4-17: (1R, 3s, 5S) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) bicyclo [3.2.1] Octane-8-on

According to general procedure B2, 3- (2,6-dichlorophenyl) -5-methyl-4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[ 1,3] dioxolane] -3-yloxy) methyl) isoxazole Int-3-17a, intermediate (1R, 3s, 5S) -3-((3- (2,6-dichlorophenyl) -5 -Methylisoxazol-4-yl) methoxy) bicyclo [3.2.1] octane-8-one Int-4-17 was synthesized.
Intermediate Int-4-18: (1R, 3r, 5S) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) bicyclo [3.2.1] Octane-8-on

According to general procedure B2, 3- (2,6-dichlorophenyl) -5-methyl-4-(((1R, 3r, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[ 1,3] dioxolane] -3-yloxy) methyl) isoxazole Int-3-17b, intermediate (1R, 3r, 5S) -3-((3- (2,6-dichlorophenyl) -5 -Methylisoxazol-4-yl) methoxy) bicyclo [3.2.1] octane-8-one Int-4-18 was synthesized.
Intermediate Int-4-19: (1R, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-methylbicyclo [3.2 .1] Octane-8-one

According to general procedure B, 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 5S) -3-methylspiro [bicyclo [3.2.1] octane-8,2 ' Starting from-[1,3] dioxolan] -3-yl) oxy) methyl) isoxazole Int-3-18, the intermediate (1R, 5S) -3-((5-cyclopropyl-3- (2 , 6-Dichlorophenyl) isoxazol-4-yl) methoxy) -3-methylbicyclo [3.2.1] octan-8-one Int-4-19 was synthesized.
Intermediate Int-4-20: (1R, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3- (difluoromethyl) bicyclo [ 3.2.1] Octane-8-on

Following general procedure B, 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 5S) -3- (difluoromethyl) spiro [bicyclo [3.2.1] octane- Starting from 8,2 ′-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole Int-3-19, the intermediate (1R, 5S) -3-((5-cyclopropyl- 3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3- (difluoromethyl) bicyclo [3.2.1] octan-8-one Int-4-20 was synthesized.
Intermediate Int-4-21: (1R, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3- (methoxymethyl) bicyclo [ 3.2.1] Octane-8-on

According to general procedure B 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 5S) -3- (methoxymethyl) spiro [bicyclo [3.2.1] octane- Starting from 8,2 ′-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole Int-3-20, intermediate (1R, 5S) -3-((5-cyclopropyl- 3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3- (methoxymethyl) bicyclo [3.2.1] octan-8-one Int-4-21 was synthesized.
Intermediate Int-4-22: (3aR, 6aS) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) hexahydropentalene-2 (1H) -ON

According to general procedure B, 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((3a′R, 6a ′S) -hexahydro-1′H-spiro [[1,3] dioxolane Starting from -2,2'-pentalene] -5'-yl) oxy) methyl) isoxazole Int-3-21, the intermediate (3aR, 6aS) -5-((5-cyclopropyl-3- ( 2,6-Dichlorophenyl) isoxazol-4-yl) methoxy) hexahydropentalen-2 (1H) -one Int-4-22 was synthesized and isolated as a single isomer. Chiral HPLC (OZ-H 4.6 × 250 mm column 5 μm; eluent: CO ₂ / MeOH 65:35, (0.2% NH ₄ OMe); flow rate: 1.95 mL / min; w = 214-359 nm; T = 40.1 ° C): Retention time 2.94 minutes (minor isomer (4%): 3.36 minutes). ¹ H-NMR (500 MHz, CDCl ₃ ) δ ppm: 7.41-7.32 (m, 3H), 4.21 (s, 2H), 3.93-3.89 (m, 1H), 2.65-2.62 (m, 2H), 2.42- 2.36 (m, 2H), 2.13-1.99 (m, 5H), 1.40-1.35 (m, 2H), 1.27-1.23 (m, 2H), 1.14-1.10 (m, 2H).
Intermediate Int-4-23: (1R, 4R) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [2.2.1] heptane -2-one

According to general procedure B, 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-(((1R, 4R) -spiro [bicyclo [2.2.1] heptane-2,2 '-[1 , 3] dioxolane] -5-yloxy) methyl) isoxazole Int-3-22 intermediate (1R, 4R) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl)) Isoxazol-4-yl) methoxy) bicyclo [2.2.1] heptan-2-one Int-4-23 was synthesized.
Intermediate Int-4-24: (1R, 3s, 5S) -3-((5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) isoxazol-4-yl) methoxy) bicyclo [3 2.1] Octane-8-one

5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) -4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8, Starting from 2 ′-[1,3] dioxolane] -3-yloxy) methyl) isoxazole Int-3-23, the intermediate (1R, 3s, 5S) -3-((5-cyclopropyl-3- ((2,6-Dimethylphenoxy) methyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-one Int-4-24 was synthesized.
Intermediate Int-4-25: (1R, 3s, 5S) -3-((3- (2,6-dichlorophenyl) -5-isopropylisoxazol-4-yl) methoxy) bicyclo [3.2.1] Octane-8-on

According to general procedure B 3- (2,6-dichlorophenyl) -5-isopropyl-4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[ 1,3] dioxolane] -3-yloxy) methyl) isoxazole Int-3-24, intermediate (1R, 3s, 5S) -3-((3- (2,6-dichlorophenyl) -5 -Isopropylisoxazol-4-yl) methoxy) bicyclo [3.2.1] octane-8-one Int-4-25 was synthesized.
Intermediate Int-4-26: (1R, 3s, 5S) -3-((3- (2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) isoxazol-4-yl) methoxy ) Bicyclo [3.2.1] octane-8-one

According to general procedure B 3- (2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) -4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1 ] Starting from octane-8,2 ′-[1,3] dioxolane] -3-yloxy) methyl) isoxazole Int-3-25, the intermediate (1R, 3s, 5S) -3-((3- (2,6-Dichlorophenyl) -5- (2-fluoropropan-2-yl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-one Int-4-26 was synthesized. .
Intermediate Int-4-27: (1R, 3s, 5S) -3-((3- (2,6-dichlorophenyl) -5- (2-hydroxypropan-2-yl) isoxazol-4-yl) methoxy ) Bicyclo [3.2.1] octane-8-one

According to general procedure B, 2- (3- (2,6-dichlorophenyl) -4-(((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[1 , 3] dioxolane] -3-yloxy) methyl) isoxazol-5-yl) propan-2-ol Int-3-26 intermediate (1R, 3s, 5S) -3-((3- (2,6-Dichlorophenyl) -5- (2-hydroxypropan-2-yl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-one Int-4-27 was synthesized. .
Intermediate Int-4-28: (1R, 3s, 5S) -3-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) bicyclo [3.2 .1] Octane-8-one

According to general procedure B2, 4-cyclopropyl-1- (2,6-dichlorophenyl) -5-((((1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′ Starting from-[1,3] dioxolane] -3-yl) oxy) methyl) -1H-pyrazole Int-3-27 intermediate (1R, 3s, 5S) -3-((4-cyclopropyl- 1- (2,6-Dichlorophenyl) -1H-pyrazol-5-yl) methoxy) bicyclo [3.2.1] octan-8-one Int-4-28 was synthesized.
Intermediate Int-4-29: 3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclo-pentanone

4-((1,4-Dioxaspiro [4.4] nonan-7-yloxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole (Int-3- (5 mL) in THF (5 mL). 28, 130 mg, 0.32 mmol) was treated with 1N HCl (5 mL) and stirred at room temperature for 30 min. The mixture was treated with saturated aqueous NaHCO ₃ and diluted with EtOAc. The phases were separated and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purify by chromatography (ISCO 12 g Gold silica, 0-1005 EtOAc / hexanes) to give the product 3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclo Pentanone Int-4-29 was obtained.
Intermediate Int-4-30: (1R, 5S) -7-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-oxabicyclo [3.3 .1] Nonan-9-one

According to general procedure B2, 4-(((1R, 5S) -3-oxaspiro [bicyclo [3.3.1] nonane-9,2 ′-[1,3] dioxolane] -7-yloxy) methyl)- Starting from 5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-3-29, the intermediate (1R, 5S) -7-((5-cyclopropyl-3- (2,6- Dichlorophenyl) isoxazol-4-yl) methoxy) -3-oxabicyclo [3.3.1] nonan-9-one Int-4-30 was synthesized.
Intermediate Int-5-1: 9-Hydroxy-1,4-dioxadispiro [4.1.3.1] undecane

Step 1: Spiro [3.3] heptane-2,6-dione in MeOH (50 mL) (synthesized according to RA Weatherhead et al., J. Org. Chem., 2009, 74, 8773) (1.0 g , 8.0 mmol), NaBH ₄ (76 mg, 2 mmol) was added at 0 ° C. The mixture was stirred for 1 h, quenched with aqueous NH ₄ Cl (10 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over _Na 2 SO _4, filtered, and concentrated 6-hydroxy-spiro [3.3] resulted heptan-2-Int-5a-1.

Step 2: To a solution of 6-hydroxyspiro [3.3] heptan-2-one Int-5a-1 (500 mg, 4.0 mmol) in toluene (50 mL) was added ethylene glycol (0.5 g, 8.0 mmol). And p-TsOH (70 mg, 0.4 mmol) was added at room temperature. The mixture was refluxed for 1 h, cooled, quenched with aqueous NaHCO ₃ (10 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to yield 9-hydroxy-1,4-dioxadispiro [4.1.3.1] undecane Int-5-1.
Intermediate Int-5-2: Spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-ol

Step 1: A solution of paraformaldehyde (15 g, 0.5 mol), acetophenone (60 g, 0.5 mol) and K ₂ CO ₃ (700 mg) in MeOH (100 mL) was stirred at room temperature for 7 days, then water (1 L). The mixture was acidified with HCl (conc) and extracted with EtOAc (4 × 500 mL). The organic layers were combined, washed with water (2 × 200 mL) and dried over anhydrous MgSO ₄ . The solvent was removed under reduced pressure. The remaining crude product, 3-methoxy-2- (methoxymethyl) -1-phenylpropan-1-one Int-5a-2, was used in the next step without purification.

Step 2: Crude 3-methoxy-2- (methoxymethyl) -1-phenylpropan-1-one Int-5a-2 was dissolved in concentrated HCl (50 mL) at room temperature, and the resulting solution was stirred at room temperature for 24 hours. Over stirring. The mixture was extracted with EtOAc (3 × 200 mL) and the organic layers were combined, washed with water (2 × 100 mL) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by column chromatography to give 3-chloro-2- (chloromethyl) -1-phenylpropan-1-one Int-5b-2.

Step 3: 3-Chloro-2- (chloromethyl) -1-phenylpropan-1-one Int-5b-2 (1.08 g, 5.0 mmol), 1- (cyclopenta-1-) in MeCN (15 mL) A solution of en-1-yl) pyrrolidine (680 mg, 5.0 mmol) and TEA (610 mg, 6.0 mmol) was heated to reflux for 1 hour. The mixture was cooled to room temperature, diluted with water (15 mL), stirred at room temperature overnight and extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried over Na ₂ SO ₄ , concentrated, and purified by column chromatography to give (1R, 5S) -3-benzoylbicyclo [3.2.1] octane-8-one Int-5c- 2 was produced.

Step 4: (1R, 5S) -3-Benzoylbicyclo [3.2.1] octan-8-one Int-5c-2 (700 mg, 3.0 mmol), ethane-1,2- in toluene (10 mL) A solution of diol (200 mg, 3.0 mmol) and p-TsOH (30 mg) was heated to reflux overnight, poured into NaHCO ₃ (saturated aqueous solution) and extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried over Na ₂ SO ₄ , concentrated, and purified by column chromatography to phenyl ((1R, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[ 1,3] dioxolane] -3-yl) methanone Int-5d-2 was obtained.

Step 5: Phenyl ((1R, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolan] -3-yl) methanone Int-5d-2 (2.07 g , 7.61 mmol), to a mixture of potassium tert-butoxide (1.23 g, 10.4 mmol) and tert-butyl alcohol (25 mL) was added hexamethylphosphoric triamide (25 mL). The resulting mixture was saturated with O ₂ with stirring at 55 ° C. After the reaction was complete, water was added and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL), dried over Na ₂ SO ₄ , concentrated, purified by column chromatography and (1R, 5S) -spiro [bicyclo [3.2.1]. Octane-8,2 ′-[1,3] dioxolane] -3-one Int-5e-2 was obtained.

Step 6: (1R, 5S) -Spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-one Int-5e in MeOH / DCM (10 mL / 40 mL) -2 (5.0 g, 18 mmol), NaBH ₄ (1.36 g, 36 mmol) was added in several portions under stirring. The mixture was stirred at room temperature overnight, poured into saturated aqueous NaHCO ₃ and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na ₂ SO ₄ , concentrated, and crude (1R, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane]- 3-ol Int-5-2 was obtained and used without further purification.
Intermediate Int-5-3: (1R, 5S) -3-oxaspiro [bicyclo [3.3.1] nonane-9,2 ′-[1,3] dioxolane] -7-ol

Step 1: ₃ -Chloro-2- (chloromethyl) -1-phenylpropan-1-one Int-5b-2 (10 g, 45.8 mmol), 1- (3,6-) in CH ₃ CN (150 mL) A solution of dihydro-2H-pyran-4-yl) pyrrolidine (7.0 g, 45.8 mmol) and TEA (5.0 g, 50.0 mmol) was heated to reflux for 1 hour, cooled to room temperature, and water (150 mL ) And stirred at room temperature overnight. The mixture was extracted with EtOAc (3 × 100 mL). The organic layers were combined, dried over Na ₂ SO ₄ , concentrated, and purified by column chromatography to give (1R, 5S) -7-benzoyl-3-oxabicyclo [3.3.1] nonane-9-one. Int-5a-3 was obtained.

Step 2: (1R, 5S) -7-benzoyl-3-oxabicyclo [3.3.1] nonan-9-one Int-5a-3 (7.8 g, 32.0 mmol) in toluene (100 mL), A solution of ethane-1,2-diol (2.4 g, 38.4 mmol) and p-TsOH (500 mg) was heated to reflux overnight, poured into NaHCO ₃ (aq) and extracted with EtOAc (3 × 100 mL). did. The organic layers were combined, dried over Na ₂ SO ₄ , concentrated, and purified by column chromatography to phenyl ((1R, 5S) -3-oxaspiro [bicyclo [3.3.1] nonane-9,2 ′. -[1,3] Dioxolane] -7-yl) methanone Int-5b-3 was obtained.

Step 3: Phenyl ((1R, 5S) -3-oxaspiro [bicyclo [3.3.1] nonane-9,2 ′-[1,3] dioxolan] -7-yl) methanone Int-5b-3 (7 To a mixture of potassium tert-butoxide (3.4 g, 30.0 mmol) and tert-butyl alcohol (100 mL) was added hexamethylphosphoric triamide (100 mL). While stirring at 55 ° C., the mixture was saturated with O ₂ . After the reaction was complete (determined by TLC), water (1 L) was added and the mixture was extracted with EtOAc (3 × 100 mL). The organic layers were combined, washed with water (2 × 100 mL), dried over Na ₂ SO ₄ , concentrated, purified by column chromatography and (1R, 5S) -3-oxaspiro [bicyclo [3.3. 1] Nonane-9,2 ′-[1,3] dioxolane] -7-one Int-5c-3 was obtained.

Step 4: (1R, 5S) -3-oxaspiro [bicyclo [3.3.1] nonane-9,2 ′-[1,3] dioxolane] -7-one Int in MeOH / DCM (10 mL / 40 mL) To a mixture of −5c-3 (1.0 g, 5.0 mmol), NaBH ₄ (760 mg, 20.0 mmol) was added in several portions at 0 ° C. The mixture was stirred at room temperature overnight, poured into NH ₄ Cl solution and extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over Na ₂ SO ₄ , concentrated, and (1R, 5S) -3-oxaspiro [bicyclo [3.3.1] nonane-9,2 ′-[1,3] dioxolane] — 7-ol Int-5-3 was obtained and used in the next step without further purification.
Intermediate Int-6-1: 2-Bromo-4-fluorobenzo [d] thiazole-6-carbonitrile

  Step 1: To a stirred solution of 4-amino-3-fluorobenzonitrile (2.0 g, 14.7 mmol) and potassium thiocyanide (5.7 g, 59 mmol) in AcOH (50 mL) in AcOH (5 mL). A solution of bromine (2.3 g, 14.7 mmol) was added over 20 minutes. The mixture was stirred at room temperature for 20 hours and poured into ice water (100 mL). Ammonium hydroxide solution (28%) was added to pH 8, stirred for 2 hours, filtered, washed with water and dried to give 4-amino-3-fluorobenzonitrile Int-6a-1. .

Step 2: 4-amino-3-fluorobenzonitrile Int-6a-1 (2.0 g, 10 mmol), tert-BuONO (1.5 g, 15 mmol) and CuBr ₂ (3.3 g, 15 mmol) in MeCN (100 mL). ) Was stirred at room temperature overnight, quenched with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over _Na 2 SO _4, filtered, and concentrated to give 2-bromo-4-fluoro-benzo [d] thiazole-6-carbonitrile Int-6-1.
Intermediate Int-6-2: 2,6-dibromo-7-fluorobenzo [d] thiazole

  Step 1: To a solution of 4-bromo-2,3-difluoroaniline (7.66 g, 36.8 mmol) in acetone (60 mL), benzoyl isothiocyanate (9.02 g, 55.2 mmol) was added dropwise with ice cooling. did. The mixture was stirred at room temperature for 18 hours. The precipitate was collected by filtration and washed with hexane. The resulting product was dried under reduced pressure to give N-((4-bromo-2,3-difluorophenyl) carbamothioyl) benzamide Int-6a-2.

Step 2: To a suspension of N-((4-bromo-2,3-difluorophenyl) carbamothioyl) benzamide Int-6a-2 (10.9 g, 29.5 mmol) in methanol (20 mL) was added 2N NaOH (148 mL, 295 mmol) was added and the mixture was heated at reflux for 1 h, cooled to room temperature, extracted with EtOAc (3 × 300 mL), washed with brine (2 × 50 mL), Na ₂ SO ₄ And concentrated to give 1- (4-bromo-2,3-difluorophenyl) thiourea Int-6b-2.

Step 3: To a solution of sodium hydride (60%; 4.01 g, 100 mmol) in dry DMF (50 mL) was added 1- (4-bromo-2,3-difluorophenyl) thiourea Int-6b-2 (6. 69 g, 25.1 mmol) was added over 15 minutes with ice cooling. The mixture was stirred at room temperature for 20 minutes, stirred at 80 ° C. for 3 hours, cooled, diluted with NH ₄ Cl saturated solution and water, extracted with EtOAc (3 × 200 mL), and brine (2 × 50 mL). Wash, dry over Na ₂ SO ₄ , concentrate, and purify by flash chromatography (EtOAc / PE = 1: 1) to give 6-bromo-7-fluorobenzo [d] thiazol-2-amine Int-6c -2 was obtained.

Step 4: To a solution of 6-bromo-7-fluorobenzo [d] thiazol-2-amine Int-6c-2 (3.71 g, 15.0 mmol) in MeCN (50 mL) was added isopentyl nitrite (2.64 g). , 22.6 mmol) was added and the solution was stirred at room temperature for 30 minutes, then CuBr (4.31 g, 30.1 mmol) was added and the mixture was stirred at room temperature overnight. EtOAc (300 mL) was added and the solution was washed with water (2 × 50 mL), brine (2 × 50 mL), dried over Na ₂ SO ₄ , concentrated and flash chromatographed (PE / EtOAc = 20: 1). To give 2,6-dibromo-7-fluorobenzo [d] thiazole Int-6-2.
Intermediate Int-6-3: 2,6-dibromo-5,7-difluorobenzo [d] thiazole

Starting from 6-bromo-5,7-difluorobenzo [d] thiazol-2-amine as described for the intermediate Int-6-2 (step 4), the synthesis gives 2,6 -Dibromo-5,7-difluorobenzo [d] thiazole Int-6-3 was obtained.
Intermediate Int-6-4: 2,6-dibromo-5-fluorobenzo [d] thiazole

Starting from 6-bromo-5-fluorobenzo [d] thiazol-2-amine as described for the intermediate Int-6-2 (step 4), the synthesis provides 2,6-dibromo. -5-Fluorobenzo [d] thiazole Int-6-4 was obtained.
Intermediate Int-6-5: 6-Bromo-4-fluorobenzo [d] thiazol-2-amine

Step 1: To a solution of 4-bromo-2-fluoroaniline (2.00 g, 10.5 mmol) in AcOH (25 mL), KSCN (4.0 g, 42.0 mmol) was added in one portion at room temperature and obtained The mixture was stirred at room temperature until it became a clear solution. Bromine (1.85 g, 10.5 mmol) in AcOH (10 mL) was then added over 15 minutes at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The precipitate formed during the reaction was removed by filtration. The filtrate was poured into water (100 mL) and basified to pH 8-9 with concentrated NH ₄ OH. The resulting precipitate was collected by suction filtration to obtain a crude product. The crude product was purified by chromatography to give 6-bromo-4-fluorobenzo [d] thiazol-2-amine Int-6a-5.

Step 2: To a mixture of copper (II) bromide (770 mg, 3.5 mmol) in MeCN (10 mL) was added tert-butyl nitrite (1.0 mL, 7.5 mmol) at 0 ° C., followed by 6-bromo-4-fluoro-benzo [d] thiazol-2-amine Int-6a-5 (800 mg, 3.2 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 20 hours and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by chromatography to give 2,6-dibromo-4-fluorobenzo [d] thiazole Int-6-5.
Intermediate Int-6-6: 2-bromoquinoline-5-carbonitrile

Step 1: To a solution of quinoline-5-carbonitrile (1.06 g, 9.60 mmol) in DCM (30 mL) was added m-CPBA (2.48 g, 14.40 mmol) at room temperature and the mixture was stirred overnight. Diluted with water and extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography (PE / EtOAc = 2: 1) to give 5-cyanoquinoline 1-oxide Int. -6a-6 was produced.

Step 2: A mixture of 5-cyanoquinoline 1-oxide Int-6a-6 (1.13 g, 6.66 mmol) and POBr ₃ (5.65 g, 20.0 mmol) was heated to 55 ° C. over 1 hour, then ice water Was added and the mixture was extracted three times with DCM. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography (PE / EtOAc = 10: 1) to give 2-bromoquinoline-5-carbohydrate. Nitrile Int-6-6 was obtained.
Intermediate Int-6-7: 6-Bromo-1-isopropyl-1H-indazole-3-carbonitrile

To a solution of 6-bromo-1H-indazole-3-carbonitrile (220 mg, 1.0 mmol) in dry DMF (5 mL) was added NaH (48 mg, 1.2 mmol, 60% suspension in mineral oil) in small portions. And the mixture was stirred at room temperature for 0.5 h. Then isopropyl iodide (200 mg, 1.2 mmol) was added and stirring was continued for 1 hour. The mixture was poured into water (20 mL) and the precipitate was collected to give the title compound 6-bromo-1-isopropyl-1H-indazole-3-carbonitrile Int-6-7, which was further Used in next step without purification.
Intermediate Int-6-8: 7- (1,3-Dioxolan-2-yl) benzo [d] thiazole

Reflux a mixture of benzo [d] thiazole-7-carbaldehyde (4.2 g, 25.6 mmol), p-TsOH (100 mg) and ethane-1,2-diol (3.0 mL) in toluene (50 mL) overnight. Allowed to cool to room temperature and diluted with EtOAc (100 mL). The solution was washed with saturated NaHCO ₃ and brine. The solution was then dried, concentrated and purified by chromatography to give compound 7- (1,3-dioxolan-2-yl) benzo [d] thiazole Int-6-8.
Intermediate Int-6-9: 6-iodoquinoline-4-carbonitrile

Step 1: 4-Chloro-6-nitroquinoline (5.0 g, 24.0 mmol), Zn (CN) ₂ (5.6 g, 48.0 mmol) and Pd (PPh ₃ ) ₄ (1 in DMF (50 mL). .16g, it was degassed mixture of 1.0mmol) with _{N 2.} The mixture was stirred at 125 ° C. overnight, cooled to room temperature and diluted with EtOAc. The mixture was then washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by chromatography to give 6-nitroquinoline-4-carbonitrile Int-6a-9.

Step 2: To a solution of 6-nitroquinoline-4-carbonitrile Int-6a-9 (2.2 g, 11.1 mmol) in MeOH (20 mL) was added Pd (OH) ₂ (200 mg) at room temperature. The reaction was stirred overnight at room temperature under H ₂ atmosphere and filtered. The filtrate was concentrated to dryness to give 6-aminoquinoline-4-carbonitrile Int-6b-9.

Step 3: To a mixture of 6-aminoquinoline-4-carbonitrile Int-6b-9 (1.83 g, 10.8 mmol) in water (10 mL) was added concentrated HCl (3 mL) at 0 ° C. to dissolve the solid did. Then a solution of NaNO ₂ (1.4 g, 20.3 mmol) in water (5 mL) was added slowly. After the solution was stirred at 0 ° C. for 20 minutes, a solution of KI (5.0 g, 30.1 mmol) in water (5 mL) was added. The reaction was stirred at room temperature for 1 hour and poured into saturated NaHCO ₃ . The mixture is extracted with EtOAc and the organic phase is washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by chromatography to give 6-iodoquinoline-4-carbonitrile Int-6-9. It was.
Intermediate Int-6-10: (5-Bromobenzo [d] isothiazol-3-yl) methanol

To a solution of methyl 5-bromobenzo [d] isothiazole-3-carboxylate (2.8 g, 10.3 mmol) in MeOH (30 mL) was added NaBH ₄ (760 mg, 20.0 mmol) slowly at room temperature, The mixture was stirred at 50 ° C. for 2 hours, concentrated, diluted with EtOAc, washed with 0.1 N HCl and brine. The organic solution was dried (Na ₂ SO ₄ ) and concentrated to give (5-bromobenzo [d] isothiazol-3-yl) methanol Int-6-10.
Intermediates Int-6-11: 6-Bromo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H- [1,2,3] triazolo [4,5-b] pyridine and 6-bromo-3 -((2- (trimethylsilyl) ethoxy) methyl) -3H- [1,2,3] triazolo [4,5-b] pyridine mixture

To a suspension of NaH (60% in mineral oil, 120 mg, 3.0 mmol) in THF (3 mL) was added 6-bromo-1H- [1,2,3] triazolo [4,5- in THF (8 mL). b] Pyridine (400 mg, 2.0 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes, then SEM-Cl (500 mg, 3.0 mmol) was added dropwise at 0 ° C. and stirring was continued for 1 hour. The reaction was quenched with NH ₄ Cl (saturated) and extracted with EtOAc (3 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over Na ₂ SO ₄ , concentrated and purified by chromatography to give Int-6-11 as 6-bromo-1-((2- (Trimethylsilyl) ethoxy) methyl) -1H- [1,2,3] triazolo [4,5-b] pyridine and 6-bromo-3-((2- (trimethylsilyl) ethoxy) methyl) -3H- [1, Obtained as a mixture of 2,3] triazolo [4,5-b] pyridine.
Intermediate Int-6-12: Ethyl 2- (5- (trifluoromethyl) oxazol-4-yl) acetate

Step 1: To a mixture of ethyl 2-isocyanoacetate (10.0 g, 88.4 mmol) and DBU (13.2 g, 88.4 mmol) in dry THF (40 mL) was added TFAA (18 mL) in dry THF (50 mL). 0.7 g, 89 mmol) was added dropwise at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for an additional 10 hours. The solvent was removed under reduced pressure and H ₂ O (100 mL) was added. The mixture was extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give ethyl 5- (trifluoromethyl) oxazole-4-carboxylate Int-6a-12.

Step 2: Stir a mixture of 5- (trifluoromethyl) oxazole-4-carboxylate Int-6a-12 (4.8 g, 23.0 mmol), 1N NaOH (30 mL) and MeOH (50 mL) at room temperature for 4 hours. did. The solvent was removed under reduced pressure and the pH was adjusted to pH = 2 with 1N HCl. The residue was extracted with EtOAc (3 × 20 mL), the organic layers were combined, dried over Na ₂ SO ₄ and then concentrated under reduced pressure to give 5- (trifluoromethyl) oxazole-4-carboxylic acid Int— 6b-12 was obtained and used directly in the next step without further purification.

Step 3: A solution of 5- (trifluoromethyl) oxazole-4-carboxylic acid Int-6b-12 (1.6 g, 8.84 mmol) in DCM (10 mL) was cooled to 0 ° C. in an ice bath, (COCl) ₂ (2.18 g, 22.1 mmol) was then added dropwise. After the addition, a catalytic amount of DMF (40 μL) was carefully added and the resulting mixture was stirred at room temperature for an additional hour. The reaction mixture was concentrated under reduced pressure and the crude 5- (trifluoromethyl) oxazole-4-carbonyl chloride Int-6c-12 was used in the next step without further purification.

Step 4: A solution of crude 5- (trifluoromethyl) oxazole-4-carbonyl chloride Int-6c-12 (2.2 g, 8.84 mmol, th.) In dry ACN / THF (15/15 mL) at 0 ° C. And TMSCHN ₂ (2.0 M in hexanes, 9.0 mL, 18 mmol) was added dropwise over 5 minutes under Ar atmosphere. The resulting solution was stirred at room temperature for 1 hour and the reaction was quenched with dilute AcOH (0.5N). The mixture was extracted with EtOAc (3 × 10 mL) and the organic layers were combined, washed with brine (2 × 10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 2-diazo-1- (5- (trifluoromethyl) oxazol-4-yl) ethane-1-one Int-6d-12.

Step 5: Solution of 2-diazo-1- (5- (trifluoromethyl) oxazol-4-yl) ethane-1-one Int-6d-12 (1.0 g, 0.49 mmol) in EtOH (5 mL) To the solution, Ag ₂ O (556 mg, 0.245 mmol) was added in several portions over 5 minutes under Ar atmosphere. The resulting solution was protected from light and heated to 50 ° C. and stirring was continued overnight. The reaction mixture was filtered through a short pad of Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give ethyl 2- (5- (trifluoromethyl) oxazol-4-yl) acetate Int-6-12.
Intermediate Int-7-1: 3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclobutanone

Step 1: To a solution of 3- (benzyloxy) cyclobutanol (356 mg, 2.00 mmol) in dry DMF (10 mL) was added NaH (60%, 160 mg, 4.00 mmol) at 0 ° C. and the mixture was mixed with 1 Stir over time. Then 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-2-3 (602 mg, 2.00 mmol) was added and the mixture was stirred at room temperature for 4 hours. Quench with aqueous NH ₄ Cl and extract three times with EtOAc. The organic portion was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography (PE / EtOAc = 8: 1) to give 4-((3- (benzyloxy)) Cyclobutoxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-7a-1 was obtained.

Step 2: 4-((3- (Benzyloxy) cyclobutoxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-7a-1 (614 mg, 1 in MeOH (20 mL) .38 mmol) was added Pd / C (150 mg) under Ar and then stirred under H ₂ overnight. The mixture was filtered and concentrated to give 3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclobutanol Int-7b-1.

Step 3: MeCN (10 mL) and _H 2 O (3 mL) in 3 - ((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclobutanol Int-7b-1 To a solution of (294 mg, 0.83 mmol), iodobenzene diacetate (869 mg, 2.70 mmol) and TEMPO (240 mg, 1.35 mmol) were added and the solution was stirred at room temperature for 2 hours, followed by aqueous Na ₂ CO ₃ solution. Quenched with and diluted with EtOAc. The organic portion was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by chromatography (PE / EtOAc = 4: 1) to give 3-((5-cyclopropyl-3- This gave (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclobutanone Int-7-1.
Intermediate Int-8-1: 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2,2-dimethylcyclohexanone

Step 1: To a solution of 1,4-dioxaspiro [4.5] decan-8-one (12.0 g, 76.5 mmol) in dry THF (120 mL), NaH (60%, 6.12 g, 153 mmol) was added. Added under Ar and the mixture was stirred for 1 h, then MeI (27.2 g, 191 mmol) was added and stirred at 10 ° C. overnight, quenched with aqueous NH ₄ Cl and diluted with EtOAc. The organic portion was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography (PE / EtOAc = 10: 1) to give 7,7-dimethyl-1,4- Dioxaspiro [4.5] decan-8-one Int-8a-1 was obtained.

Step 2: To a solution of 7,7-dimethyl-1,4-dioxaspiro [4.5] decan-8-one Int-8a-1 (5.76 g, 31.3 mmol) in MeOH (55 mL) was added NaBH _4. (3.57 g, 93.8 mmol) was added and the mixture was stirred at room temperature overnight, quenched with aqueous NH ₄ Cl and diluted with EtOAc. The organic portion was washed with brine, dried over _Na 2 SO _4, filtered, and concentrated, 7,7-dimethyl-1,4-dioxaspiro [4.5] decan-8-ol Int-8b-1 Got.

Step 3: To a solution of 7,7-dimethyl-1,4-dioxaspiro [4.5] decan-8-ol Int-8b-1 (500 mg, 2.69 mmol) in dry DMF (8 mL) was added NaH (60 %, 215 mg, 5.38 mmol) was added at 0 ° C. and the mixture was stirred for 1 h, then benzyl bromide (549 mg, 3.23 mmol) was added, stirred at room temperature overnight and quenched with aqueous NH ₄ Cl solution And extracted three times with EtOAc. The combined organic portions were washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography (PE / EtOAc = 10: 1) to give 8- (benzyloxy) -7. , 7-dimethyl-1,4-dioxaspiro [4.5] decane Int-8c-1.

Step 4: To a solution of 8- (benzyloxy) -7,7-dimethyl-1,4-dioxaspiro [4.5] decane Int-8c-1 (404 mg, 1.46 mmol) in acetone (10 mL) was added HCl. (2N, 1 mL) was added at room temperature and the mixture was stirred for 1 h. The solvent was then removed and the residue was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 4- (benzyloxy) -3,3-dimethylcyclohexanone Int-8d-1.

Step 5: To a solution of 4- (benzyloxy) -3,3-dimethylcyclohexanone Int-8d-1 (265 mg, 1.14 mmol) in MeOH (8 mL) was added NaBH ₄ (181 mg, 4.77 mmol). The mixture was stirred at room temperature overnight, quenched with aqueous NH ₄ Cl and diluted with EtOAc. The organic portion was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 4- (benzyloxy) -3,3-dimethylcyclohexanol Int-8e-1.

Step 6: To a solution of 4- (benzyloxy) -3,3-dimethylcyclohexanol Int-8e-1 (229 mg, 0.98 mmol) in dry DMSO (10 mL) was added NaH (60%, 78 mg, 1.96 mmol). ) Was added at 0 ° C. and the mixture was stirred for 1 h, then 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-2-3 (602 mg, 2. 00 mmol) was added and the mixture was stirred at room temperature overnight, quenched with aqueous NH ₄ Cl and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography (PE / EtOAc = 6: 1) to give 4-(((4- (benzyl Oxy) -3,3-dimethylcyclohexyl) oxy) methyl) -5-cyclopropyl-3- (2,6-dichloro-phenyl) isoxazole Int-8f-1 was obtained.

Step 7: 4-((((4- (benzyloxy) -3,3-dimethylcyclohexyl) oxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int in MeOH (8 mL) To a solution of −8f-1 (218 mg, 0.44 mmol) was added Pd black (50 mg) under N ₂ followed by formic acid (0.5 mL). The mixture was stirred overnight and filtered, then the filtrate was washed with aqueous NaHCO _{3 and} extracted three times with EtOAc. The combined organic portions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl. ) Methoxy) -2,2-dimethylcyclohexanol Int-8g-1.

Step 8: To a solution of PCC (148 mg, 0.69 mmol) in DCM (10 mL) was added 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2. , 2-dimethylcyclohexanol Int-8g-1 (186 mg, 0.46 mmol) was added and the solution was stirred at room temperature for 1 h, filtered, concentrated and chromatographed (PE / EtOAc = 4: 1). Purification gave racemic 4-((5-cyclopropyl-3- (2,6-dichloro-phenyl) isoxazol-4-yl) methoxy) -2,2-dimethylcyclohexanone Int-8-1. It was.
Intermediate Int-8-2: 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3,3-dimethylcyclohexanone

Step 1: To a solution of 7,7-dimethyl-1,4-dioxaspiro [4.5] decan-8-ol Int-8b-1 (372 mg, 2.00 mmol) in dry DMSO (5 mL) was added NaH (60% , 160 mg, 4.00 mmol) was added at 0 ° C. and the mixture was stirred for 1 h. Then 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-2-3 (602 mg, 2.00 mmol) was added and stirred at room temperature overnight and NH ₄ Cl Quench with aqueous solution and extract three times with EtOAc. The combined organic portions were washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography (PE / EtOAc = 8: 1) to give 5-cyclopropyl-3- ( 2,6-Dichlorophenyl) -4-(((7,7-dimethyl-1,4-dioxaspiro [4.5] decan-8-yl) oxy) methyl) isoxazole Int-8a-2 was obtained.

Step 2: 5-Cyclopropyl-3- (2,6-dichlorophenyl) -4-(((7,7-dimethyl-1,4-dioxaspiro [4.5] decan-8-yl in acetone (5 mL) To a solution of) oxy) methyl) isoxazole Int-8a-2 (375 mg, 0.83 mmol) was added HCl (2N, 1 mL) at room temperature and the mixture was stirred for 1 h. The solvent was then removed and the residue was diluted with water and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give racemic 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole- 4-yl) methoxy) -3,3-dimethylcyclohexanone Int-8-2 was obtained.
Intermediate Int-8-3: (1R, 3S, 5s, 7s) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) adamantan-2-one

To a suspension of NaH (120 mg, 3.0 mmol; 60% in mineral oil) in THF (10 mL) was added 5-hydroxyadamantan-2-one (500 mg, 3.0 mmol) in dry THF (3 mL) at 0 ° C. Added at. The mixture was stirred at 0 ° C. for 1.5 hours and then 4- (bromomethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole (Example 1, step) in dry THF (5 mL). 1) (1.15 g, 3.3 mmol) was added at 0 ° C. and the mixture was stirred at reflux overnight, cooled, quenched with saturated NH ₄ Cl and extracted with EtOAc (3 × 20 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over Na ₂ SO ₄ , concentrated, purified by silica gel chromatography to give (1R, 3S, 5s, 7s) -5-((5- Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) adamantan-2-one Int-8-3 was obtained.
Intermediate Int-9-1: (1R, 5S) -3-Methylspiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-ol

(1R, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-one (500 mg, 2.75 mmol) Int-5e in THF (10 mL) -2 solution was added methylmagnesium bromide (4 mL, 1 M in THF) at 0 ° C. The mixture was warmed to room temperature, stirred overnight, diluted with saturated NH ₄ Cl (30 mL) and extracted with EtOAc (3 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by silica gel column (PE / EtOAc = 5: 1) to give (1R, 5S) − One isomer of 3-methylspiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-ol Int-9-1 was obtained.
Intermediate Int-9-2: (1R, 5S) -3- (difluoromethyl) spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-ol

Step 1: (1R, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-one in THF (20 mL) / HMPA (2.0 mL) To a solution of (500 mg, 2.75 mmol) Int-5e-2 (1.0 g, 5.5 mmol) and PhSO ₂ CF ₂ H (1.1 g, 5.5 mmol), LiHMDS (5.5 mL, 1M in THF). Was added dropwise at −78 ° C. under N ₂ . The mixture was stirred vigorously at −78 ° C. for 2 h, diluted with saturated aqueous NH ₄ Cl (30 mL) at −78 ° C. and then extracted with Et ₂ O (3 × 20 mL). The combined organic phases were dried over MgSO ₄ , concentrated and purified by column chromatography (PE / EtOAc = 6: 1) to give (1R, 5S) -3- (difluoromethyl) spiro [bicyclo [3.2. .1] Octane-8,2 ′-[1,3] dioxolane] -3-ylbenzenesulfonate Int-9a-2 was obtained.

Step 2: (1R, 5S) -3- (difluoromethyl) spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-yl in dry MeOH (50 mL) To a solution of benzenesulfonate Int-9a-2 (1.7 g, 4.5 mmol) and Na ₂ HPO ₄ (1.9 g, 13.5 mmol), Na / Hg amalgam (10 wt% Na in Hg, sodium net content) 13.5 mmol) was added at −20 ° C. under N ₂ . The mixture was stirred at −20 ° C. to 0 ° C. for 1 hour. The liquid phase was decanted and the solid residue was washed with Et ₂ O. The solid was then treated with elemental sulfur powder to destroy the mercury residue. The combined organic phase solvents were removed in vacuo, diluted with brine (50 mL) and extracted three times with Et ₂ O. The combined ether phases were dried over MgSO ₄ , concentrated and purified by chromatography (PE / EtOAc = 5: 1) to give (1R, 5S) -3- (difluoromethyl) spiro [bicyclo [3.2. 1] One isomer of octane-8,2 ′-[1,3] dioxolane] -3-ol Int-9-2 was obtained. ¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 5.48 (t, J = 56.5 Hz, 1H), 4.87 (s, 1H), 3.85 (s, 4H), 1.95-1.89 (m, 4H), 1.84 -1.81 (m, 2H), 1.67-1.64 (m, 2H), 1.58-1.55 (m, 2H).
Intermediate Int-9-3: (1R, 5S) -3- (methoxymethyl) spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-ol

Step 1: To a solution of trimethyl-oxo-sulfonium iodide (500 mg, 2.2 mmol) in DMSO (10 mL) was added NaH (60% in mineral oil) (182 mg, 4.5 mmol) at 0 ° C. under N _2. did. The mixture was stirred at room temperature for 30 minutes and then (1R, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] in DMSO (4.0 mL). 3-one (500mg, 2.75mmol) Int-5e -2 (376mg, 2.0mmol) was added and the mixture was stirred at room temperature _overnight, quenched with H 2 O (30mL), and extracted with EtOAc. The organic phase was washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography (PE / EtOAc = 5: 1) to give oxirane Int-9a-3. It was.

Step _2: CH 3 OH (15mL) solution of the oxirane Int-9a-3 (324mg, 1.6mmol) to a solution of _was added CH 3 ONa (268mg, 4.9mmol) . The mixture was stirred at reflux overnight, concentrated and purified by flash chromatography (PE / EtOAc = 3: 1) to give (1R, 5S) -3- (methoxy-methyl) spiro [bicyclo [3.2.1]. One isomer of octane-8,2 ′-[1,3] dioxolane] -3-ol Int-9-3 was obtained. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 3.95-3.90 (m, 4H), 3.37 (s, 3H), 3.11 (s, 2H), 2.21 (s, 1H), 1.98-1.95 (m, 4H) , 1.92-1.68 (m, 6H).
Intermediate Int-9-4: (1R, 5S) -8-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane -3-On

Step 1: (1R, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-one Int-5e in MeOH / DCM (10 mL / 40 mL) -B (7.0 g, 38.5 mmol), NaBH ₄ (1.46 g, 38.5 mmol) was added in several portions at 0 ° C. The mixture was stirred overnight at room temperature, poured into NH ₄ Cl solution and extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over Na ₂ SO ₄ , concentrated, and purified by column chromatography (EtOAc / PE = 1: 3) to give pure exo isomer (1R, 3s, 5S) -spiro [bicyclo [ 3.2.1] Octane-8,2 ′-[1,3] dioxolane] -3-ol Int-9a-4 was produced.

Step 2: Compound (1R, 3s, 5S) -spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] -3-ol Int-9a in dry DMF (20 mL) -4 (1.2 g, 6.5 mmol) was added NaH (60% in oil; 782 mg, 19.5 mmol) slowly at 0 ° C., then the mixture was stirred at room temperature for 40 min and BnBr (1. 67 g, 9.77 mmol) was added. The mixture was stirred at room temperature for 3 hours, diluted slowly with saturated NH ₄ Cl solution (40 mL) and extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over Na ₂ SO ₄ , concentrated, purified by column chromatography (EtOAc / PE = 1: 8), (1R, 3s, 5S). -3- (Benzyloxy) spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] Int-9b-4 was obtained. Chiral HPLC (OJ-H 4.6 × 250 mm column 5 μm; eluent: CO ₂ / MeOH 4: 1, (0.2% NH ₄ OMe); flow rate: 2.4 mL / min; w = 214-359 nm; T = 39.8 ° C): Retention time 3.40 minutes.

  Step 3: Compound (1R, 3s, 5S) -3- (benzyloxy) spiro [bicyclo [3.2.1] octane-8,2 ′-[1,3] dioxolane] Int- in acetone (30 mL) To 9b-4 (1.52 g, 5.54 mmol) was added 2N HCl (8 mL) and the mixture was stirred at 60 ° C. for 2 h, concentrated and by column chromatography (EtOAc / PE = 1: 6). Purification gave (1R, 3s, 5S) -3- (benzyloxy) bicyclo [3.2.1] octan-8-one Int-9c-4.

Step 4: To the compound (1R, 3s, 5S) -3- (benzyloxy) bicyclo [3.2.1] octan-8-one Int-9c-4 (892 mg, 3.87 mmol) in MeOH (20 mL). , NaBH ₄ (366 mg, 9.68 mmol) was added at 0 ° C. and the mixture was stirred at room temperature for 2 h, concentrated and purified by column chromatography (EtOAc / PE = 1: 3) to give (1R, 3s, 5S) -3- (benzyloxy) bicyclo [3.2.1] octane-8-ol Int-9d-4 was obtained as a single isomer. Chiral HPLC (AD-H 4.6 × 250 mm column 5 μm; eluent: CO _{2 /} MeOH 7: _{3, (} 0.2% NH ₄ OMe); flow rate: 2.1 mL / min; w = 214-359 nm; T = 39.9 ° C.): Retention time 4.37 minutes.

Step 5: To a suspension of NaH (60% in mineral oil; 395 mg, 9.88 mmol) in dry DMSO (25 mL) is added (1R, 3s, 5S) -3- (benzyloxy) in dry DMSO (6 mL). Bicyclo [3.2.1] octane-8-ol Int-9d-4 was added at 0 ° C. The mixture was stirred at room temperature for 1 hour, then 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole (1.50 g, 4.94 mmol) was added at 0 ° C. The mixture was stirred at room temperature for 4 hours, quenched with NH ₄ Cl (saturated) and extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over Na ₂ SO ₄ , concentrated and purified by chromatography (EtOAc / PE = 1: 5) to give 4-(((((1R, 3s, 5S) -3- (Benzyloxy) bicyclo [3.2.1] octane-8-yl) oxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-9e- 4 was obtained.

Step 6: Compound 4-(((((1R, 3s, 5S) -3- (benzyloxy) bicyclo [3.2.1] octane-8-yl) oxy) methyl) -5- in MeOH (30 mL) To cyclopropyl-3- (2,6-dichlorophenyl) isoxazole Int-9e-4 (830 mg, 1.67 mmol) was added HCOOH (2.0 mL) and Pd (400 mg) and the mixture was added under N ₂ . Stir at room temperature for 8 hours. The mixture was filtered, the solvent removed and purified by column chromatography (EtOAc / DCM = 1: 10) to give (1R, 3s, 5S) -8-((5-cyclopropyl-3- (2,6 -Dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-3-ol Int-9f-4 was obtained.

  Step 7: Compound (1R, 3s, 5S) -8-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2 in acetone (30 mL) .1] To octan-3-ol Int-9f-4 (543 mg, 1.33 mmol) was added IBX (745 mg, 2.66 mmol) and the mixture was stirred at reflux for 2 hours, filtered to remove the solvent. Single isomer (1R, 5S) -8-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane- 3-one Int-9-4 was obtained.

Intermediate Int-10a / b: (1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8- (1 -((2- (trimethylsilyl) ethoxy) methyl) -1H- [1,2,3] triazolo [4,5-b] pyridin-6-yl) bicyclo [3.2.1] octan-8-ol and (1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8- (3-((2- (trimethylsilyl)) Ethoxy) methyl) -3H- [1,2,3] triazolo [4,5-b] pyridin-6-yl) bicyclo [3.2.1] octan-8-ol

According to general procedure 1G, (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane -8-one (Int-4-14a) and 6-bromo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H- [1,2,3] triazolo [4,5-b] pyridine and 6 Starting from a mixture of -bromo-3-((2- (trimethylsilyl) ethoxy) methyl) -3H- [1,2,3] triazolo [4,5-b] pyridine Int-6-11 by synthesis, ((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8- (1-((2- (trimethylsilyl) D Xyl) methyl) -1H- [1,2,3] triazolo [4,5-b] pyridin-6-yl) bicyclo [3.2.1] octan-8-ol and (1R, 3s, 5S, 8r) ) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8- (3-((2- (trimethylsilyl) ethoxy) methyl) -3H- [ 1,2,3] triazolo [4,5-b] pyridin-6-yl) bicyclo [3.2.1] octane-8-ol Int-10a / b was obtained as a separated isomer (SEM regioisomerism). Body is not assigned).
Intermediate Int-11-11: (3a′R, 6a ′S) -hexahydro-1′H-spiro [[1,3] dioxolane-2,2′-pentalene] -5′-ol

Step 1: To a solution of (3as, 6as) -tetrahydropentalene-2,5 (1H, 3H) -dione (500 mg, 3.62 mmol) in toluene (60 mL), ethylene glycol (226 mg, 3.65 mmol) and TsOH (20 mg) was added and the mixture was stirred at 130 ° C. for 3 hours, diluted with water and extracted with EtOAc. The organic portion was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and (3a′R, 6a ′S) -tetrahydro-1′H-spiro [[1,3] dioxolane-2 , 2′-pentalene] -5 ′ (3′H) -one Int-11a-1.

Step 2: (3a′R, 6a ′S) -Tetrahydro-1′H-spiro [[1,3] dioxolane-2,2′-pentalene] -5 ′ (3′H) — in MeOH (8 mL) To a solution of On Int-11a-1 (495 mg, 2.72 mmol) was added NaBH ₄ (259 mg, 6.80 mmol) and the mixture was stirred at room temperature overnight, quenched with aqueous NH ₄ Cl and diluted with EtOAc . The organic portion was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated, purified by flash chromatography (PE / EtOAc = 9: 1) and (3a′R, 6a ′S) − Hexahydro-1′H-spiro [[1,3] dioxolane-2,2′-pentalene] -5′-ol Int-11-1 was obtained.
Intermediate Int-11-2: (1R, 4R) -spiro [bicyclo [2.2.1] heptane-2,2 ′-[1,3] dioxolane] -5-ol

  Step 1: Similar to that described for intermediate Int-11a-1, using (1R, 4R) -bicyclo [2.2.1] heptane-2,5-dione as starting material, intermediate The product (1R, 4R) -spiro [bicyclo [2.2.1] heptane-2,2 ′-[1,3] dioxolane] -5-one Int-11a-2 was synthesized.

Step 2: (1R, 4R) -spiro [bicyclo [2.2.1] heptane-2,2 '-[1,3] dioxolane] as described for the intermediate Int-11-1. -5-one Int-11a-2 as starting material, intermediate (1R, 4R) -spiro [bicyclo [2.2.1] heptane-2,2 '-[1,3] dioxolane]- 5-ol Int-11-2 was synthesized.
Intermediate Int-12-1: Methyl 1- (3-bromo-5-fluorophenoxy) cyclopropanecarboxylate

Step 1: To a solution of 3-bromo-5-fluorophenol (1.0 g, 5.26 mmol) in DMF (20 mL) was added potassium carbonate (0.73 g, 5.26 mmol) and methyl 2,4-dibromobutanoate. (1.36 g, 5.26 mmol) was added and the mixture was heated at 60 ° C. for 3 h, cooled to room temperature and extracted with EtOAc (3 × 100 mL). The organic portion was washed with brine, dried over Na ₂ SO ₄ , concentrated, purified by column chromatography (PE / EA = 10: 1) and methyl 4-bromo-2- (3-bromo-5 -Fluorophenoxy) butanoate Int-12a-1.

Step 2: A solution of methyl 4-bromo-2- (3-bromo-5-fluorophenoxy) butanoate Int-12a-1 (500 mg, 1.36 mmol) in THF (15 mL) was cooled to −15 ° C. and potassium Tert-butoxide (183 mg, 1.63 mmol) was added. The cooling bath was removed and the mixture was stirred at room temperature for 5 h, poured into EtOAc (50 mL) and 50 mL water and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , concentrated, purified by column chromatography (PE / EA = 10: 1) and methyl 1- (3-bromo-5-fluorophenoxy). ) Cyclopropanecarboxylate Int-12-1.
Intermediate Int-13-1: 2- (2-bromothiazol-4-yl) ethanol

To a solution of methyl 2- (2-bromothiazol-4-yl) acetate (100 mg, 0.43 mmol) in MeOH (50 mL) was added NaBH ₄ (82 mg, 2.15 mmol) and the mixture was stirred at room temperature overnight. Quench with aqueous NH ₄ Cl (30 mL) and extract with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL) and concentrated under vacuum to give 2- (2-bromothiazol-4-yl) ethanol Int-13-1.

  The compounds of the present invention can be prepared by methods known to those skilled in the art. The following examples are merely intended to represent examples of the present invention and are not intended to limit the present invention in any way.

Example 1
(1s, 4s) -1- (5-Bromobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclo Hexanol (1)

Step 1: 4- (Bromomethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole (1a)
A solution of phosphorus tribromide (10.48 g, 38.7 mmol, 3.64 mL) in DCM (5 mL) was added to (5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole in DCM (145 mL). -4-yl) methanol (5.0 g, 17.60, mmol) was added dropwise at 0 ° C. under an argon atmosphere. After the addition, the mixture was stirred at 0 ° C. for another 20 minutes, followed by stirring at room temperature for 20 minutes. The mixture was quenched by slowly adding it to a stirred aqueous saturated NaHCO ₃ solution (250 mL) at 0 ° C. and stirring was continued at 0 ° C. for an additional 10 minutes to reduce gas evolution. The layers were separated and the aqueous material was extracted with DCM (100 mL). The combined organics were washed with brine (75 mL), dried over Na ₂ SO ₄ and the solvent removed under reduced pressure to give the title compound 1a (3.01 g, 49%).

Step 2: 4-((1,4-Dioxaspiro [4.5] decan-8-yloxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole (1b)
Sodium hydride (0.629 g, 15.73 mmol, 60%) of 1,4-dioxaspiro [4.5] decan-8-ol (2.370 g, 14.98 mmol) in ACN (anhydrous) (40 mL). To the stirred solution was added at room temperature and then stirred at room temperature for 15 minutes. Intermediate 1a (2.60 g, 7.49 mmol) was then added without solvent and the mixture was stirred at 40 ° C. for 2.5 hours. The mixture was cooled to room temperature and quenched with saturated aqueous NaHCO ₃ (20 mL). ACN was removed under reduced pressure. The remaining aqueous phase was extracted with EtOAc (2 × 25 mL). The combined organics were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and the solvent removed under reduced pressure. The oily residue was purified by flash column chromatography on silica using gradient elution with 5% to 50% EtOAc in heptane. Fractions containing the product were combined and the solvent removed under reduced pressure to give the title compound 1b (2.20 g, 75% purity by LC / MS, 45.7%).

Step 3: 4-((5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone (1c)
An aqueous solution of hydrogen chloride (1.0 M, 20 mmol, 20.0 mL) was added to a stirred solution of intermediate 1b (2.20 g, 3.89 mmol) in acetone (40.0 mL) at room temperature. The mixture was then stirred and heated at 40 ° C. for 30 minutes. The mixture was cooled to room temperature and basified to pH˜8 by the addition of saturated aqueous NaHCO ₃ (30 mL). Acetone was removed under reduced pressure and the residual aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent removed under reduced pressure. The oily residue was purified by flash column chromatography on silica using gradient elution with 5% to 65% EtOAc in heptane. Fractions containing the product were combined and the solvent was removed under reduced pressure to give the title compound 1c (1.60 g, 99%).

Step 4: (1s, 4s) -1- (5-Bromobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) Methoxy) cyclohexanol (1)
A solution of n-butyllithium (4.37 mmol, 1.75 mL, 2.5 M in hexane) was added to 2,5-dibromobenzo [d] thiazole (1.281 g, 4.37 mmol) in anhydrous THF (35 mL). To the stirred solution was added dropwise over 5 minutes at −78 ° C. under a nitrogen atmosphere. The mixture was stirred at −78 ° C. for 20 minutes and a solution of intermediate 1c (1.33 g, 3.50 mmol) in anhydrous THF (5.0 mL) was added to the mixture at −78 ° C. over 5 minutes under a nitrogen atmosphere. Added dropwise. The mixture was then stirred at −78 ° C. for 1 hour and quenched by the addition of water (2.0 mL). The cooling was removed and the quenched reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The mixture was concentrated to remove most of the THF. The aqueous phase was partitioned between saturated aqueous NaHCO ₃ (25 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2 × 15 mL) and the combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and the solvent removed under reduced pressure. The oily residue was purified by flash column chromatography on silica using gradient elution with 10% to 100% EtOAc in heptane. The two product fractions were pooled and concentrated to dryness, and each product was purified again by flash column chromatography on silica using gradient elution with 0% to 2.0% MeOH in DCM. . Pooled major product fractions were concentrated to dryness to give the title compound (1: major isomer, 1.14 g, 55%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.12 (s, 1H), 8.03 (d, 1H, J = 8.5 Hz), 7.67-7.49 (m, 4H), 6.18 (s, 1H) , 4.31 (s, 2H), 3.26-3.18 (m, 1H), 2.39-2.31 (m, 1H), 1.86-1.75 (m, 4H), 1.72-1.61 (m, 2H), 1.49-1.32 (m, 2H), 1.18-1.05 (m, 4H). MS: m / z [M + H] ⁺ 593/595/597.

  2D NMR experiments show that the two oxygen substituents in the cyclohexyl ring are oriented cis with respect to each other.

(Example 2)
(1r, 4r) -1- (5-Bromobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclo Hexanol (2)

The title compound was isolated as a minor product from Step 4 of Example 1 (2:75 mg, 3.6%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.165 (s, 1H), 8.03 (d, 1H, J = 8.5 Hz), 7.65-7.51 (m, 3H), 7.49-7.43 (m, 1H), 6.11 (s, br, 1H), 4.28 (s, 2H), 3.44-3.32 (m, 1H), 2.46-2.34 (m, 1H), 2.08-1.80 (m, 2H), 1.76-1.453 ( m, 6H), 1.30-1.03 (m, 4H). MS: m / z [M + H] ⁺ 593/595/597.

(Example 3)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-5- Carbonitrile (3)

A suspension of the compound of Example 1 (250 mg, 0.421 mmol) and zinc cyanide (49.4 mg, 0.421 mmol) in anhydrous DMF (5.0 mL) in a microwave vial at room temperature was charged with nitrogen gas. Flush well for 10 minutes. Next, Pd ₂ (dba) ₃ (38.5 mg, 0.042 mmol) and xanthophos (24.34 mg, 0.042 mmol) were added without solvent and the mixture was flushed again thoroughly with nitrogen gas for 5 minutes. The vial was capped and heated in a microwave at 110 ° C. for 1 hour. The mixture was partitioned between saturated aqueous NaHCO ₃ (25 mL) and EtOAc (25 mL). The aqueous layer was extracted again with EtOAc (1 × 25 mL). The combined organic phases were washed with brine (3 × 10 mL), dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica using gradient elution with 20% to 70% EtOAc in heptane. Fractions containing the product were combined and the solvent removed under reduced pressure to give the title compound Example 3 (138 mg, 51%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 8.45 (s, 1H), 8.29 (d, 1H, J = 8.3 Hz), 7.80-7.75 (m, 1H), 7.68-7.54 (m, 3H), 6.29 (s, 1H), 4.31 (s, 2H), 3.36-3.20 (m, 1H), 2.39-2.32 (m, 1H), 1.82-1.76 (m, 4H), 1.73-1.62 (m, 2H), 1.49-1.33 (m, 2H), 1.19-1.07 (m, 4H). MS: m / z [M + H] ⁺ 540/542.

Example 4
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-5- Carboxylic acid (4)

A 40% aqueous solution of NaOH (900 mg, 9.00 mmol, 0.90 mL) was added to a stirred solution of Example 3 (360 mg, 0.666 mmol) in EtOH (5.0 mL) in an 8 mL screw-cap vial at room temperature. did. The vial was sealed and heated at 85 ° C. for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between 1M aqueous HCl (20 mL) and EtOAc (15 mL). The aqueous layer was extracted again with EtOAc (1 × 15 mL) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent removed under reduced pressure to give the crude title compound. This was purified by preparative HPLC. Fractions containing product were combined and ACN was removed under reduced pressure. The remaining aqueous solution was carefully acidified to pH ˜4 by dropwise addition of 1M aqueous HCl. A precipitate forms during the addition. The solid is filtered off, rinsed with water (2 × 5 mL), collected and dried in high vacuum at room temperature overnight to give the title compound 4e (122 mg, 24%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 13.2 (s, br, 1H), 8.39 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.68-7.54 (m, 2H), 6.20 (s, 1H), 4.32 (s, 2H), 3.30-3.18 (m, 1H), 2.40-2.31 (m, 1H), 1.91-1.76 (m, 4H), 1.73-1.63 ( m, 2H), 1.51-1.36 (m, 2H), 1.18-1.07 (m, 4H) .MS: m / z [M-H] - 557/559.

(Example 5)
2-((1r, 4r) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-5 Carboxylic acid (5)

Example 5 was prepared from Example 2 following a procedure similar to that described for Example 4. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ ppm: 13.2 (s, br, 1H), 8.44 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.63-7.57 (m, 2H), 7.50 -7.43 (m, 1H), 6.13 (s, 1H), 4.29 (s, 2H), 3.46 (s, 1H), 2.45-2.35 (m , 1H), 2.06-1.95 (m, 2H), 1.75-1.64 (m, 2H), 1.63-1.47 (m, 4H), 1.21-1.10 (m, 4H). MS: m / z [MH] ^- 557/559.

General Procedure 1A for the Synthesis of Example 6/7

A solution of ketone (1.0 eq) and bromide (1.2 eq) in dry THF is cooled to −78 ° C., then n-BuLi (1.33 eq) is added dropwise and the mixture is added at −78 ° C. Stir for 2 h, quench with saturated NH ₄ Cl and extract 3 times with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated, and the residue was purified by preparative TLC or flash chromatography to give major isomer 6 and minor isomer 7. (Minor isomers may not be isolated.)

(Example 6-1) and (Example 7-1)
(1s, 4s) -1- (6-Bromobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methoxy) Cyclohexanol (6-1) and (1r, 4r) -1- (6-bromobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) iso Oxazol-4-yl) methoxy) cyclohexanol (7-1)

Following general procedure 1A, intermediate 4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-1 (420 mg, 1.2 mmol) and Starting from 2,6-dibromobenzo [d] thiazole, the title compound (1s, 4s) -1- (6-bromobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (4,4-Difluorocyclohexyl) isoxazol-4-yl) methoxy) cyclohexanol (6-1) and (1r, 4r) -1- (6-bromobenzo [d] thiazol-2-yl) -4- ( (5-Cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methoxy) cyclohexanol ( -1) were synthesized and purified by preparative _{TLC (CH 2 Cl 2 / MeOH} = 20: 1) and purified by.

(Example 6-2)
(1s, 4s) -1- (6-Bromo-5-fluorobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole- 4-yl) methoxy) cyclohexanol

  Following the general procedure 1A, the intermediates 4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-5 and 2,6-dibromo- Starting from 5-fluorobenzo [d] thiazole Int-6-4, the title compound (1s, 4s) -1- (6-bromo-5-fluorobenzo [d] thiazol-2-yl) -4- ( (5-Cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) cyclohexanol (6-2) was synthesized and prepared by preparative TLC (PE / EtOAc = 2: 1). Purified. The minor isomer was not isolated.

(Example 6-3)
(1s, 4s) -1- (6-Bromo-5-fluorobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4- Yl) methoxy) cyclohexanol

  Following general procedure 1A, intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 and 2,6-dibromo-5- Starting from fluorobenzo [d] thiazole Int-6-4, the title compound (1s, 4s) -1- (6-bromo-5-fluorobenzo [d] thiazol-2-yl) -4-((5 -Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanol (6-3) was synthesized and purified by preparative TLC (PE / EtOAc = 2: 1). The minor isomer was not isolated.

(Example 6-4)
(1s, 4s) -1- (6-Bromo-5,7-difluorobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole- 4-yl) methoxy) cyclohexanol

  Following general procedure 1A, intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 and 2,6-dibromo-5, Starting from 7-difluoro-benzo [d] thiazole Int-6-3, the title compound (1s, 4s) -1- (6-bromo-5,7-difluorobenzo [d] thiazol-2-yl)- 4-((5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanol (6-4) was synthesized and preparative TLC (PE / EtOAc = 2: 1) Purified by The minor isomer was not isolated.

(Example 6-5)
(1s, 4s) -1- (6-Bromo-7-fluorobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4- Yl) methoxy) cyclohexanol

  Following the general procedure 1A, the intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 and 2,6-dibromo-7- Starting from fluorobenzo [d] thiazole Int-6-2, the title compound (1s, 4s) -1- (6-bromo-7-fluorobenzo [d] thiazol-2-yl) -4-((5 -Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanol (6-5) was synthesized and purified by preparative TLC (PE / EtOAc = 2: 1). The minor isomer was not isolated.

(Example 6-6)
1- (6-Bromobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclopentanol

A solution of 2,6-dibromobenzo [d] thiazole (105 mg, 0.36 mmol) in THF (2.2 mL) was cooled to −78 ° C. in a dry ice / acetone bath in a dry vial under nitrogen. Then 1.6M n-butyllithium solution in hexane (0.22 mL, 0.36 mmol) was added dropwise and the solution was stirred at −78 ° C. for 20 minutes. Then 3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclopentanone (Int-4-29, 105 mg, dissolved in THF (0.5 mL). 0.29 mmol) was added dropwise and the reaction was stirred at −78 ° C. for 1 h. The reaction was quenched with water, allowed to warm to room temperature and then treated with EtOAc. The phases were separated and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by column chromatography (ISCO, 12 g, GOLD silica, 0-100% EtOAc / hexanes) gave the target compound 1- (6-bromobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl -3- (2,6-Dichlorophenyl) isoxazol-4-yl) methoxy) cyclopentanol (6-6) was obtained.

General Procedure 1B for the Synthesis of Example 8

A solution of bromide (1.0 eq), ZnCN ₂ (1.0-1.5 eq), Pd ₂ (dba) ₃ (0.1 eq), xanthophos (0.1 eq) in DMF under Ar. Stir at 110 ° C. overnight. The mixture was partitioned between saturated aqueous NaHCO ₃ and EtOAc. The aqueous layer was extracted again with EtOAc. The combined organic phases were washed 3 times with brine, dried over Na ₂ SO ₄ , evaporated and purified by preparative TLC or flash chromatography to give Example 8-1.

Alternative General Procedure 1B2 for the Synthesis of Example 8
A suspension of bromide (1 eq) and zinc cyanide (2 eq) in DMF (about 40 vol) was thoroughly flushed with Ar for 10 min at room temperature in a microwave vial. Pd ₂ (dba) ₃ (20 mol%) and xanthophos (20 mol%) were then added under Ar. The resulting mixture was heated in a microwave oven at 110 ° C. for 1-2 h, then quenched with NH ₄ Cl (saturated) and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel chromatography to give the cyanide product.

一般的手順１Ｂに従って、実施例（１ｓ，４ｓ）−１−（６−ブロモベンゾ［ｄ］チアゾール−２−イル）−４−（（５−シクロプロピル−３−（４，４−ジフルオロシクロヘキシル）イソオキサゾール−４−イル）メトキシ）シクロヘキサノール（６−１）から出発して、表題化合物２−（（１ｓ，４ｓ）−４−（（５−シクロプロピル−３−（４，４−ジフルオロシクロヘキシル）イソオキサゾール−４−イル）メトキシ）−１−ヒドロキシシクロヘキシル）ベンゾ［ｄ］チアゾール−６−カルボニトリル（８−１）を合成した。 (Example 8-1)
2-((1s, 4s) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6 -Carbonitrile

According to general procedure 1B, example (1s, 4s) -1- (6-bromobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) iso Starting from oxazol-4-yl) methoxy) cyclohexanol (6-1), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl)) Isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (8-1) was synthesized.

一般的手順１Ｂに従って、実施例（１ｒ，４ｒ）−１−（６−ブロモベンゾ［ｄ］チアゾール−２−イル）−４−（（５−シクロプロピル−３−（４，４−ジフルオロシクロヘキシル）イソオキサゾール−４−イル）メトキシ）シクロヘキサノール（７−１）から出発して、表題化合物２−（（１ｒ，４ｒ）−４−（（５−シクロプロピル−３−（４，４−ジフルオロシクロヘキシル）イソオキサゾール−４−イル）メトキシ）−１−ヒドロキシシクロヘキシル）ベンゾ［ｄ］チアゾール−６−カルボニトリル（８−２）を合成した。 (Example 8-2)
2-((1r, 4r) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6 -Carbonitrile

According to general procedure 1B, example (1r, 4r) -1- (6-bromobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) iso Starting from oxazol-4-yl) methoxy) cyclohexanol (7-1), the title compound 2-((1r, 4r) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl)) Isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (8-2) was synthesized.

一般的手順１Ｂに従って、実施例（１ｓ，４ｓ）−１−（６−ブロモ−５−フルオロベンゾ［ｄ］チアゾール−２−イル）−４−（（５−シクロプロピル−３−（２−（ジフルオロメトキシ）フェニル）イソオキサゾール−４−イル）メトキシ）シクロヘキサノール（６−２）から出発して、表題化合物２−（（１ｓ，４ｓ）−４−（（５−シクロプロピル−３−（２−（ジフルオロメトキシ）フェニル）イソオキサゾール−４−イル）メトキシ）−１−ヒドロキシシクロヘキシル）−５−フルオロベンゾ［ｄ］チアゾール−６−カルボニトリル（８−３）を合成した。¹H-NMR (500 MHz, CDCl₃): δ 7.82 (d, J = 8.5 Hz, 1H), 7.68-7.65 (m, 1H), 7.57-7.55 (m, 1H), 7.51-7.47 (m, 1H), 7.35-7.30 (m, 2H), 6.48 (t, J = 74.3 Hz, 1H), 4.44 (s, 2H), 3.42-3.38 (m, 1H), 2.17-1.89 (m, 7H), 1.70-1.64 (m, 2H), 1.24-1.13 (m, 4H), ヒドロキシルプロトンは分割されていない。 (Example 8-3)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5-fluorobenzo [ d] thiazole-6-carbonitrile

According to general procedure 1B, example (1s, 4s) -1- (6-bromo-5-fluorobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2- ( Starting from difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) cyclohexanol (6-2), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2) -(Difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5-fluorobenzo [d] thiazole-6-carbonitrile (8-3) was synthesized. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.82 (d, J = 8.5 Hz, 1H), 7.68-7.65 (m, 1H), 7.57-7.55 (m, 1H), 7.51-7.47 (m, 1H ), 7.35-7.30 (m, 2H), 6.48 (t, J = 74.3 Hz, 1H), 4.44 (s, 2H), 3.42-3.38 (m, 1H), 2.17-1.89 (m, 7H), 1.70- 1.64 (m, 2H), 1.24-1.13 (m, 4H), hydroxyl protons are not resolved.

一般的手順１Ｂに従って、実施例（１ｓ，４ｓ）−１−（６−ブロモ−５−フルオロベンゾ［ｄ］チアゾール−２−イル）−４−（（５−シクロプロピル−３−（２，６−ジクロロフェニル）イソオキサゾール−４−イル）メトキシ）シクロヘキサノール（６−３）から出発して、表題化合物２−（（１ｓ，４ｓ）−４−（（５−シクロプロピル−３−（２，６−ジクロロフェニル）イソオキサゾール−４−イル）メトキシ）−１−ヒドロキシシクロヘキシル）−５−フルオロベンゾ［ｄ］チアゾール−６−カルボニトリル（８−４）を合成した。 (Example 8-4)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5-fluorobenzo [d] Thiazole-6-carbonitrile

According to general procedure 1B, example (1s, 4s) -1- (6-bromo-5-fluorobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6 Starting from -dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanol (6-3), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6) -Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5-fluorobenzo [d] thiazole-6-carbonitrile (8-4) was synthesized.

一般的手順１Ｂ２に従って、実施例（１Ｒ，３ｓ，５Ｓ，８ｒ）−８−（６−ブロモベンゾ［ｄ］チアゾール−２−イル）−３−（（５−シクロプロピル−３−（２，６−ジクロロフェニル）イソオキサゾール−４−イル）メトキシ）ビシクロ［３．２．１］オクタン−８−オール（１５−１）から出発して、表題化合物２−（（１Ｒ，３ｓ，５Ｓ，８ｒ）−３−（（５−シクロプロピル−３−（２，６−ジクロロフェニル）イソオキサゾール−４−イル）メトキシ）−８−ヒドロキシビシクロ［３．２．１］オクタン−８−イル）ベンゾ［ｄ］チアゾール−６−カルボニトリル（８−５）を合成した。¹H-NMR (400 MHz, DMSO-d₆): δ 8.70 (d, J = 0.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.88 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 7.67-7.56 (m, 3H), 6.52 (br s, 1H), 4.28 (s, 2H), 3.54-3.48 (m, 1H), 2.40-2.34 (m, 3H), 1.85-1.77 (m, 4H), 1.63-1.60 (m, 2H), 1.43-1.41 (m, 2H), 1.19-1.09 (m, 4H).ＭＳ（ＥＳＩ）：ｍ／ｚ５６６．１（Ｍ＋１）^＋。 (Example 8-5)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) benzo [d] thiazole-6-carbonitrile

Following the general procedure 1B2, the example (1R, 3s, 5S, 8r) -8- (6-bromobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2,6- Starting from dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol (15-1), the title compound 2-((1R, 3s, 5S, 8r) -3 -((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole- 6-carbonitrile (8-5) was synthesized. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.70 (d, J = 0.8 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.88 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 7.67-7.56 (m, 3H), 6.52 (br s, 1H), 4.28 (s, 2H), 3.54-3.48 (m, 1H), 2.40-2.34 (m, 3H), 1.85- 1.77 (m, 4H), 1.63-1.60 (m, 2H), 1.43-1.41 (m, 2H), 1.19-1.09 (m, 4H). MS (ESI): m / z 566.1 (M + 1) ⁺ .

一般的手順１Ｂ２に従って、実施例（１Ｒ，３ｒ，５Ｓ，８ｒ）−８−（６−ブロモベンゾ［ｄ］チアゾール−２−イル）−３−（（５−シクロプロピル−３−（２，６−ジクロロフェニル）イソオキサゾール−４−イル）メトキシ）ビシクロ［３．２．１］オクタン−８−オール（１５−２）から出発して、表題化合物２−（（１Ｒ，３ｒ，５Ｓ，８ｒ）−３−（（５−シクロプロピル−３−（２，６−ジクロロフェニル）イソオキサゾール−４−イル）メトキシ）−８−ヒドロキシビシクロ［３．２．１］オクタン−８−イル）ベンゾ［ｄ］チアゾール−６−カルボニトリル（８−６）を合成した。 (Example 8-6)
2-((1R, 3r, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) benzo [d] thiazole-6-carbonitrile

Following the general procedure 1B2, the example (1R, 3r, 5S, 8r) -8- (6-bromobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2,6- Starting from dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol (15-2), the title compound 2-((1R, 3r, 5S, 8r) -3 -((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole- 6-carbonitrile (8-6) was synthesized.

(Example 8-7)
4-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) -3-fluorobenzonitrile

In accordance with General Procedure 1B2, Example (1R, 3s, 5S, 8r) -8- (4-Bromo-2-fluorophenyl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) iso Starting from oxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol (15-3), the title compound 4-((1R, 3s, 5S, 8r) -3-(( 5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -3-fluorobenzonitrile (8- 7) was synthesized.
(Example 8-8)
3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) benzonitrile

According to General Procedure 1B2, Example (1R, 3s, 5S, 8r) -8- (3-Bromophenyl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4- Yl) methoxy) bicyclo [3.2.1] octan-8-ol (15-4) starting from the title compound 3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl -3- (2,6-Dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzonitrile (8-8) was synthesized.
(Example 8-9)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

According to general procedure 1B2, the example (1R, 3s, 5S, 8r) -8- (6-bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- Starting from (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol (15-6), the title compound 2-((1R, 3s, 5S , 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl)- 4-Fluorobenzo [d] thiazole-6-carbonitrile (8-9) was synthesized. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.57 (d, J = 1.0 Hz, 1H), 7.95 (dd, J = 1.0 Hz, J = 10.5 Hz, 1H), 7.64-7.62 (m, 2H ), 7.57-7.53 (m, 1H), 6.54 (s, 1H), 4.27 (s, 2H), 3.50-3.48 (m, 1H), 2.38-2.32 (m, 1H), 2.24-2.17 (m, 4H ), 1.62-1.55 (m, 6H), 1.17-1.09 (m, 4H).
(Example 8-10)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3. 2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

According to general procedure 1B2, the example (1R, 3s, 5S, 8r) -8- (6-bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- Starting from (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol (15-7), the title compound 2-((1R, 3s , 5S, 8r) -3-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8 -Yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (8-10) was synthesized.
(Example 8-11)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

According to general procedure 1B2, the example (1R, 3s, 5S, 8r) -8- (6-bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- Starting from (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol (15-8), the title compound 2-(( 1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2 .1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (8-11) was synthesized.
(Example 8-12)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6 Carbonitrile

Example (1s, 4s) -1- (6-Bromobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole) according to general procedure 1B2 Starting from -4-yl) methoxy) cyclohexanol (15-9), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole) -4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (8-12) was synthesized.
(Example 8-13)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [d] Thiazole-6-carbonitrile

According to general procedure 1B2, example (1s, 4s) -1- (6-bromo-4-fluorobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6 Starting from -dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanol (15-10), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6) -Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carbonitrile (8-13) was synthesized.
(Example 8-14)
2-((1R, 2r, 3S, 5s, 7s) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyadamantane-2- Yl) benzo [d] thiazole-6-carbonitrile

According to General Procedure 1B2, Example (1R, 2r, 3S, 5s, 7s) -2- (6-Bromobenzo [d] thiazol-2-yl) -5-((5-cyclopropyl-3- (2, Starting from 6-dichlorophenyl) isoxazol-4-yl) methoxy) adamantan-2-ol (23a), the title compound 2-((1R, 2r, 3S, 5s, 7s) -5-((5-cyclo Propyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyadamantan-2-yl) benzo [d] thiazole-6-carbonitrile (8-14) was synthesized.
(Example 8-15)
2-((1R, 2s, 3S, 5s, 7s) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyadamantane-2- Yl) benzo [d] thiazole-6-carbonitrile

According to general procedure 1B2, example (1R, 2s, 3S, 5s, 7s) -2- (6-bromo-benzo [d] thiazol-2-yl) -5-((5-cyclopropyl-3- ( Starting from 2,6-dichlorophenyl) isoxazol-4-yl) methoxy) adamantan-2-ol (23b), the title compound 2-((1R, 2s, 3S, 5s, 7s) -5-((5 -Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyadamantan-2-yl) benzo [d] thiazole-6-carbonitrile (8-15) was synthesized. .
(Example 8-16)
2-((1R, 3s, 5S, 8r) -3-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -8-hydroxybicyclo [3. 2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

In accordance with General Procedure 1B2, Example (1R, 3s, 5S, 8r) -8- (6-Bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((4-cyclopropyl-1- Starting from (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -bicyclo [3.2.1] octan-8-ol (15-24), the title compound 2-((1R, 3s, 5S, 8r) -3-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane- 8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (8-16) was synthesized.
(Example 8-17)
2- (3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclopentyl) benzo [d] thiazole-6-carbonitrile

In a microwave vial, 1- (6-bromobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclo Put pentanol (6-6, 92 mg, 0.16 mmol), zinc cyanide (26 mg, 0.22 mmol), Pd ₂ (dba) ₃ (15 mg, 0.02 mmol), and xanthophos (9 mg, 0.02 mmol). It was. The vial was sealed, evacuated and filled with nitrogen three times. DMF (4 mL) was added and the mixture was microwaved at 100 ° C. for 30 minutes in a microwave reactor. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove most of the DMF, then diluted with EtOAc and water and filtered through celite. The phases were separated and the organic layer was washed 3 times with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by column chromatography (ISCO 12 g GOLD silica, 0-70% EtOAc / hexanes) gave the product 2- (3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4- Yl) methoxy) -1-hydroxycyclopentyl) benzo [d] thiazole-6-carbonitrile (8-17) was obtained.

General Procedure 1C for the Synthesis of Example 9 and Example 10

Cool a solution of ketone (1.0 eq) and bromide (1.0 to 1.2 eq) in dry THF to −78 ° C. then add n-BuLi (1.0 to 1.2 eq) dropwise. The mixture was stirred at −78 ° C. for 2 h, quenched with saturated NH ₄ Cl and extracted three times with EtOAc. The combined organic layers were washed with brine, dried, filtered and concentrated, and the residue was purified by preparative TLC or flash chromatography to give major isomer 9 and minor isomer 10. (Minor isomers may not be isolated.)

(Example 9-1)
2-((1s, 4s) -4-((5-cyclopropyl-3- (spiro [2.5] octan-6-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [ d] thiazole-6-carbonitrile

  Following general procedure 1C, intermediate 4-((5-cyclopropyl-3- (spiro [2.5] octan-6-yl) isoxazol-4-yl) methoxy) cyclohexanone (Int-4-2) and Starting from 2-bromobenzo [d] thiazole-6-carbonitrile, the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (spiro [2.5] octane-6- Yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-1) was synthesized (the minor isomer was not isolated).

(Example 9-2a) and (Example 9-2b)
2- (6-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyspiro [3.3] heptan-2-yl) benzo [d] Thiazole-6-carbonitrile (9-2a, first eluting enantiomer) and 2- (6-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2 -Hydroxyspiro [3.3] heptan-2-yl) benzo [d] thiazole-6-carbonitrile (9-2b, second eluting enantiomer)

Following the general procedure 1C, the intermediate 6-((5-cyclopropyl-3- (2,6-dichloro-phenyl) isoxazol-4-yl) methoxy) spiro [3.3] heptan-2-one Int- Starting from 4-3 (300 mg) and 2-bromobenzo [d] thiazole-6-carbonitrile (184 mg), a racemate was obtained, which was preparative TLC (CH ₂ Cl ₂ / MeOH = 20: 1). Purified by Separation of enantiomers by chiral HPLC revealed 2- (6-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyspiro [3.3] heptane- 2-yl) benzo [d] thiazole-6-carbonitrile (9-2a, eluting first) and enantiomer 2- (6-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole- 4-yl) methoxy) -2-hydroxyspiro [3.3] heptan-2-yl) benzo [d] thiazole-6-carbonitrile (9-2b, eluting second) was obtained.
(Example 9-3)
4-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -3-fluorobenzonitrile

Following the general procedure 1C, the intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 and 4-bromo-3-fluorobenzo Starting from a nitrile, the title compound 4-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -3-Fluorobenzonitrile (9-3) was synthesized (the minor isomer was not isolated).
(Example 9-4)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) isonicotinonitrile

From the intermediate 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 and 2-bromoisonicotinonitrile according to general procedure 1C Starting from the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) isonicoti Nononitrile (9-4) was synthesized (the minor isomer was not isolated).
(Example 9-5)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [ d] thiazole-6-carbonitrile

Following the general procedure 1C, the intermediates 4-((5-cyclopropyl-3- (2- (difluoro-methoxy) phenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-5 and 2-bromo-4 Starting from the fluorobenzo [d] thiazole-6-carbonitrile Int-6-1, the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy ) Phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-5) was synthesized (the minor isomer was not isolated) .
(Example 9-6)
(1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- (2-fluoro-4- (hydroxymethyl) phenyl) cyclo Hexanol

Following the general procedure 1C, intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 and (4-bromo-3-fluoro Starting from phenyl) methanol, the title compound (1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- (2-fluoro -4- (Hydroxymethyl) phenyl) cyclohexanol (9-6) was synthesized (the minor isomer was not isolated). ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 7.66-7.65 (m, 2H), 7.60-7.52 (m, 2H), 7.07 (d, J = 7.5 Hz, 1H), 6.99 (d, J = 13.0 Hz, 1H), 5.25-5.23 (m, 1H), 4.96 (s, 1H), 4.45 (d, J = 5.5 Hz, 2H), 4.31 (s, 2H), 3.18-3.13 (m, 1H) 2.37-2.34 (m, 1H), 1.89-1.84 (m, 2H), 1.54-1.47 (m, 6H), 1.16-1.10 (m, 4H). LCMS (ESI): m / z 506.1 (M + 1) ⁺ .
(Example 9-7)
(1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- (2-fluoro-5- (hydroxymethyl) phenyl) cyclo Hexanol

According to general procedure 1C, intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 and (3-bromo-4-fluoro Starting from phenyl) methanol, the title compound (1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- (2-fluoro -5- (Hydroxymethyl) phenyl) cyclohexanol (9-7) was synthesized (the minor isomer was not isolated). ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 7.55 (dd, J = 7.8 Hz, J = 1.8 Hz, 1H), 7.44-7.42 (m, 2H), 7.36-7.33 (m, 1H), 7.25-7.23 (m 1H), 7.02-6.98 (m, 1H), 4.65 (s, 2H), 4.37 (s, 2H), 3.29-3.25 (m, 1H), 2.21-2.18 (m, 1H), 2.05 -1.98 (m, 2H), 1.78-1.73 (m, 4H), 1.67-1.62 (m, 2H), 1.30-1.27 (m, 2H), 1.15-1.11 (m, 2H), hydroxyl protons are split Absent. LCMS (ESI): m / z 506.0 (M + 1) ^<+> .
(Example 9-8)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole- 6-carbonitrile

Following the general procedure 1C, the intermediates 4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-5 and 2-bromobenzo [d] Starting from thiazole-6-carbonitrile, the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy ) -1-Hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-8) was synthesized (the minor isomer was not isolated).
(Example 9-9)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6 Carbonitrile

Following the general procedure 1C, the intermediates 4-((5-cyclopropyl-3- (2-cyclo-propylphenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-6 and 2-bromobenzo [d] thiazole Starting from -6-carbonitrile, the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazol-4-yl) methoxy) -1 -Hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-9) was synthesized (the minor isomer was not isolated).
(Example 9-10)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6 -Carbonitrile

Following the general procedure 1C, the intermediate 4-((5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-7 and 2-bromobenzo [d] thiazole Starting from -6-carbonitrile, the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazol-4-yl) methoxy)- 1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-10) was synthesized (the minor isomer was not isolated).
(Example 9-11)
2-((1s, 4s) -4-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole- 6-carbonitrile

According to general procedure 1C, intermediates 4-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) cyclohexanone Int-4-8 and 2-bromobenzo [d] Starting from thiazole-6-carbonitrile, the title compound 2-((1s, 4s) -4-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy ) -1-Hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-11) was synthesized (the minor isomer was not isolated).
(Examples 9-12)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole -6-carbonitrile

Following general procedure 1C, intermediates 4-((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-9 and 2-bromobenzo [d Starting from thiazole-6-carbonitrile, the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) ) Methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-12) was synthesized (the minor isomer was not isolated).
(Example 9-13)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole- 6-carbonitrile

According to general procedure 1C, intermediates 4-((5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-10 and 2-bromobenzo [d] Starting from thiazole-6-carbonitrile, the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazol-4-yl) methoxy ) -1-Hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-13) was synthesized (the minor isomer was not isolated).
(Examples 9-14)
2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d ] Thiazole-6-carbonitrile

Following the general procedure 1C, the intermediate 4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-11 and 2-bromobenzo [D] Starting from thiazole-6-carbonitrile, the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazole) -4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-14) was synthesized (the minor isomer was not isolated).
(Examples 9-15)
2-((1s, 4s) -4-((4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazol-5-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] Thiazole-6-carbonitrile

Following the general procedure 1C, the intermediates 4-((4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazol-5-yl) methoxy) cyclohexanone Int-4-12 and 2-bromobenzo [ d] Starting from thiazole-6-carbonitrile, the title compound 2-((1s, 4s) -4-((4-cyclopropyl-1- (2- (difluoro-methoxy) phenyl) -1H-pyrazole- 5-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-15) was synthesized (the minor isomer was not isolated).
(Example 9-16)
2-((1s, 4s) -4-((3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropylisoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d ] Thiazole-6-carbonitrile

Following general procedure 1C, intermediates 4-((3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropylisoxazol-4-yl) methoxy) cyclohexanone Int-4-13 and 2-bromobenzo [D] Starting from thiazole-6-carbonitrile, the title compound 2-((1s, 4s) -4-((3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropylisoxazole) -4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-16) was synthesized (the minor isomer was not isolated).
(Examples 9-17)
2-((1s, 3s) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclobutyl) -4-fluorobenzo [d ] Thiazole-6-carbonitrile

Following the general procedure 1C, the intermediates 3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclobutanone Int-7-1 and 2-bromo-4-fluorobenzo [D] Starting from thiazole-6-carbonitrile (Int-6-1), the title compound 2-((1s, 3s) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl)) Isoxazol-4-yl) methoxy) -1-hydroxycyclobutyl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-17) was synthesized (the minor isomer was not isolated).
(Examples 9-18)
2-((1S, 4R) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxy-2,2-dimethylcyclohexyl) -4 -Fluorobenzo [d] thiazole-6-carbonitrile

According to general procedure 1C, intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2,2-dimethylcyclohexanone Int-8-1 and 2- Starting from bromo-4-fluorobenzo [d] thiazole-6-carbonitrile (Int-6-1), the racemic title compound 2-((1S, 4R) -4-((5-cyclopropyl- 3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxy-2,2-dimethylcyclohexyl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-18) Synthesized (the minor isomer was not isolated).
(Examples 9-19)
2-((1S, 4R) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxy-3,3-dimethylcyclohexyl) -4 -Fluorobenzo [d] thiazole-6-carbonitrile

Following general procedure 1C, intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3,3-dimethylcyclohexanone Int-8-2 and 2- Starting from bromo-4-fluorobenzo [d] thiazole-6-carbonitrile (Int-6-1), the racemic title compound 2-((1S, 4R) -4-((5-cyclopropyl- 3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxy-3,3-dimethylcyclohexyl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-19) Synthesized (the minor isomer was not isolated).
(Example 9-20)
2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4- Fluorobenzo [d] thiazole-6-carbonitrile

Following general procedure 1C, intermediates 4-((5-cyclopropyl-3- (3,5-dichloro-pyridin-4-yl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-11 and 2- Starting from bromo-4-fluorobenzo [d] thiazole-6-carbonitrile (Int-6-1), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- ( 3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-20) was synthesized (minor). The isomer was not isolated).
(Example 9-21)
6-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -1-methyl-1H-indole -3-carbonitrile

Following the general procedure 1C, the intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 and 6-bromo-1-methyl- Starting from 1H-indole-3-carbonitrile, the title compound 6-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy ) -1-Hydroxycyclohexyl) -1-methyl-1H-indole-3-carbonitrile (9-21) was synthesized (the minor isomer was not isolated).
(Example 9-22)
7-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-3-carbonitrile

Following the general procedure 1C, the intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 and 7-bromoquinoline-3-carbohydrate Starting from the nitrile, the title compound 7-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) Quinoline-3-carbonitrile (9-22) was synthesized (the minor isomer was not isolated).
(Examples 9-23)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-5-carbonitrile

Following the general procedure 1C, the intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 and 2-bromoquinoline-5-carbo Starting from the nitrile Int-6-6, the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy)- 1-Hydroxycyclohexyl) quinoline-5-carbonitrile (9-23) was synthesized (no minor isomer was isolated).
(Examples 9-24)
6-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -1-isopropyl-1H-indazole -3-carbonitrile

Following the general procedure 1C, the intermediates 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone Int-4-4 and 6-bromo-1-isopropyl- Starting from 1H-indazole-3-carbonitrile Int-6-7, the title compound 6-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole- 4-yl) methoxy) -1-hydroxycyclohexyl) -1-isopropyl-1H-indazole-3-carbonitrile (9-24) was synthesized (the minor isomer was not isolated).
(Examples 9-25)
2-((3aR, 6aS) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyoctahydropentalen-2-yl)- 4-Fluorobenzo [d] thiazole-6-carbonitrile

According to general procedure 1C, intermediate (3aR, 6aS) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) hexahydropentalene-2 (1H) Starting from the -one Int-4-22 and 2-bromo-4-fluorobenzo [d] thiazole-6-carbonitrile Int-6-1, the title compound 2-((3aR, 6aS) -5-(( 5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyoctahydropentalen-2-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-25) was synthesized (the minor isomer was not isolated).
(Example 9-26)
4-((3aR, 6aS) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyoctahydropentalen-2-yl)- 3-Fluorobenzonitrile

According to general procedure 1C, intermediate (3aR, 6aS) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) hexahydropentalene-2 (1H) Starting from the -one Int-4-22 and 4-bromo-3-fluorobenzonitrile, the title compound 4-((3aR, 6aS) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) ) Isoxazol-4-yl) methoxy) -2-hydroxyoctahydropentalen-2-yl) -3-fluorobenzonitrile (9-26) was synthesized (the minor isomer was not isolated).
(Examples 9-27) and (Examples 10-27)
2-((1R, 2S, 4R) -5-((5-cyclopropyl-3- (2,6-dichloro-phenyl) isoxazol-4-yl) methoxy) -2-hydroxybicyclo [2.2. 1] Heptan-2-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

According to general procedure 1C, (1R, 4R) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [2.2.1] heptane-2 Starting from the -one Int-4-23 and 4-bromo-3-fluorobenzonitrile, the title compound 2-((1R, 2S, 4R) -5-((5-cyclopropyl-3- (2,6 -Dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxybicyclo [2.2.1] heptan-2-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile as the major isomer 9- Synthesized as 27 and minor isomer 10-27. The isomers were separated by preparative TLC (DCM / MeOH = 20: 1) in a ratio of approximately 10: 1.
(Example 9-28)
Methyl 1- (3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [ 3.2.1] Octane-8-yl) -5-fluorophenoxy) cyclopropanecarboxylate

Following the general procedure 1C, the intermediate (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1 Starting from octan-8-one (Int-4-14a) and methyl 1- (3-bromo-5-fluorophenoxy) cyclopropanecarboxylate (Int-12-1), the title compound methyl 1- (3 -((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1 ] Octane-8-yl) -5-fluorophenoxy) cyclopropanecarboxylate (9-28) was synthesized (the minor isomer was not isolated).
(Example 9-29)
3- (3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3 2.1] octane-8-yl) phenyl) -2,2-dimethylpropanenitrile

Following the general procedure 1C, the intermediate (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1 Starting from octan-8-one (Int-4-14a) and 3- (3-bromophenyl) -2,2-dimethylpropanenitrile, the title compound 3- (3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) phenyl) -2,2-Dimethylpropanenitrile (9-29) was synthesized (the minor isomer was not isolated). LCMS (ESI): m / z 564.8 (M + 1) ^<+> .
(Example 9-30)
(1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8- (4- (2-hydroxyethyl) thiazole -2-yl) bicyclo [3.2.1] octane-8-ol

Following the general procedure 1C, the intermediate (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1 Starting from octan-8-one (Int-4-14a) and 2- (2-bromothiazol-4-yl) ethanol (Int-13-1), the title compound (1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8- (4- (2-hydroxyethyl) thiazol-2-yl) bicyclo [3. 2.1] Octane-8-ol (9-30) was synthesized (no minor isomer was isolated). ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 7.65 (d, J = 8.0 Hz, 2H), 7.59-7.56 (m, 1H), 7.20 (s, 1H), 5.89 (s, 1H), 4.61 (t, J = 5.3 Hz, 1H), 4.26 (s, 2H), 3.68-3.64 (m, 2H), 3.48-3.42 (m, 1H), 2.79 (t, J = 7.0 Hz, 2H), 2.37 -2.33 (m, 1H), 2.24 (s, 2H), 1.80-1.76 (m, 2H), 1.63-1.52 (m, 4H), 1.34-1.29 (m, 2H), 1.17-1.09 (m, 4H) LCMS (ESI): m / z 635.1 (M + H) ⁺ .
(Example 9-31)
2-((1R, 5S, 9s) -7-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -9-hydroxy-3-oxabicyclo [3. 3.1] Nonan-9-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

According to general procedure 1C, (1R, 5S) -7-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-oxabicyclo [3.3.1 Starting from nonan-9-one Int-4-30 and 4-bromo-3-fluorobenzonitrile Int-6-1, the title compound 2-((1R, 5S, 9s) -7-((5- Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -9-hydroxy-3-oxabicyclo [3.3.1] nonan-9-yl) -4-fluorobenzo [d ] Thiazole-6-carbonitrile (9-31) was synthesized.
General Procedure 1D for the Synthesis of Example 11

To a solution of nitrile (1.0 eq) in EtOH was added 40% aqueous NaOH and the mixture was stirred at 85 ° C. for 2 h. The mixture was acidified with 4M HCl and extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , evaporated, and the residue was purified by preparative TLC or preparative HPLC to give Example 11.
(Example 11-1)
2-((1s, 4s) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6 -Carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl according to general procedure 1D ) Starting from benzo [d] thiazole-6-carbonitrile (8-1), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) )) Isooxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-1 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.10 (br s, 1H), 8.70 (d, J = 1.5 Hz, 1H), 8.04-7.98 (m, 2H), 6.26 (br s, 1H ), 4.50 (s, 2H), 3.54-3.50 (m, 1H), 2.93 (t, J = 11.0 Hz, 1H), 2.23-2.19 (m, 1H), 2.12-1.94 (m, 12H), 1.73- 1.66 (m, 4H), 1.07-0.96 (m, 4H). LCMS (ESI): m / z 533.2 (M + 1) ⁺ .
(Example 11-2)
2-((1r, 4r) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6 -Carboxylic acid

Example 2-((1r, 4r) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl according to general procedure 1D ) Starting from benzo [d] thiazole-6-carbonitrile (8-2), the title compound 2-((1r, 4r) -4-((5-cyclopropyl-3- (4,4-difluorocyclohexyl) ) Isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-2 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.10 (br s, 1H), 8.70 (d, J = 1.5 Hz, 1H), 8.03-8.01 (m, 1H), 7.95 (d, J = 9.0 Hz, 1H), 6.26 (br s, 1H), 4.41 (s, 2H), 3.74 (s, 1H), 2.98 (t, J = 10.8 Hz, 1H), 2.22-2.13 (m, 3H), 2.11 -1.88 (m, 10H), 1.78-1.65 (m, 4H), 1.08-0.97 (m, 4H). LCMS (ESI): m / z 533.2 (M + 1) ⁺ .
(Example 11-3)
2-((1s, 4s) -4-((5-cyclopropyl-3- (spiro [2.5] octan-6-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [ d] thiazole-6-carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (spiro [2.5] octan-6-yl) isoxazol-4-yl) methoxy) according to general procedure 1D Starting from -1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-1), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (spiro [2.5] Octane-6-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-3 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.06 (br s, 1H), 8.70 (d, J = 1.0 Hz, 1H), 8.04-7.98 (m, 2H), 6.27 (br s, 1H ), 4.44 (s, 2H), 3.53-3.49 (m, 1H), 2.76-2.72 (m, 1H), 2.20-2.19 (m, 1H), 2.02-1.88 (m, 8H), 1.79-1.62 (m , 6H), 1.06-0.97 (m, 6H), 0.31-0.22 (m, 4H). LCMS (ESI): m / z 523.2 (M + 1) ⁺ .
(Example 11-4a)
2- (6-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyspiro [3.3] heptan-2-yl) benzo [d] Thiazole-6-carboxylic acid

Following the general procedure 1D, the first eluting isomer Example 2- (6-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyspiro [ 3.3] Starting from heptan-2-yl) benzo [d] thiazole-6-carbonitrile (9-2a), the title compound 2- (6-((5-cyclopropyl-3- (2,6 -Dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyspiro [3.3] heptan-2-yl) benzo [d] thiazole-6-carboxylic acid 11-4a was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.10 (br s, 1H), 8.67 (s, 1H), 8.04-8.00 (m, 2H), 7.66-7.63 (m, 2H), 7.55 ( t, J = 8.0 Hz, 1H), 6.66 (s, 1H), 4.13-4.08 (m, 2H), 3.78-3.75 (m, 1H), 2.69-2.57 (m, 2H), 2.36-2.23 (m, 5H), 1.73-1.62 (m, 2H), 1.17-1.09 (m, 4H). LCMS (ESI): m / z 571.1 (M + H) ⁺ . Chiral HPLC (OZ-H 4.6 × 250 mm column 5 μm; eluent: CO ₂ / MeOH 65:35, (0.5% NH ₄ OH); flow rate: 1.95 mL / min; w = 214-359 nm; T = 39.9 ° C): Retention time 11.02 minutes.
(Example 11-4b)
2- (6-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyspiro [3.3] heptan-2-yl) benzo [d] Thiazole-6-carboxylic acid

The second eluting isomer Example 2- (6-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyspiro according to general procedure 1D Starting from [3.3] heptan-2-yl) benzo [d] thiazole-6-carbonitrile (9-2b), the title compound 2- (6-((5-cyclopropyl-3- (2, 6-Dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyspiro [3.3] heptan-2-yl) benzo [d] thiazole-6-carboxylic acid 11-4b was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.10 (br s, 1H), 8.67 (s, 1H), 8.04-8.00 (m, 2H), 7.66-7.63 (m, 2H), 7.55 ( t, J = 8.0 Hz, 1H), 6.66 (s, 1H), 4.13-4.08 (m, 2H), 3.78-3.75 (m, 1H), 2.69-2.57 (m, 2H), 2.36-2.23 (m, 5H), 1.73-1.62 (m, 2H), 1.17-1.09 (m, 4H). LCMS (ESI): m / z 571.1 (M + H) ⁺ . Chiral HPLC (OZ-H 4.6 × 250 mm column 5 μm; eluent: CO ₂ / MeOH 65:35, (0.5% NH ₄ OH); flow rate: 1.95 mL / min; w = 214-359 nm; T = 39.9 ° C): Retention time 9.56 minutes.
(Example 11-5)
4-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -3-fluorobenzoic acid

Example 4-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) according to general procedure 1D Starting from -3-fluorobenzonitrile (9-3), the title compound 4-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4- Yl) methoxy) -1-hydroxycyclohexyl) -3-fluorobenzoic acid 11-5 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.16 (br s, 1H), 7.74-7.53 (m, 6H), 5.27 (br s, 1H), 4.31 (s, 2H), 3.19-3.15 (m, 1H), 2.38-2.33 (m, 1H), 1.92-1.86 (m, 2H), 1.57-1.45 (m, 6H), 1.18-1.10 (m, 4H). LCMS (ESI): m / z 520 .1 (M + H) ⁺
(Example 11-6)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) isonicotinic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) according to general procedure 1D Starting from isonicotinonitrile (9-4), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) Methoxy) -1-hydroxycyclohexyl) isonicotinic acid 11-6 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.60 (br s, 1H), 8.55 (dd, J = 5.0, J = 0.5 Hz, 1H), 8.11 (s, 1H), 7.66-7.57 ( m, 4H), 5.15 (br s, 1H), 4.31 (s, 2H), 3.19-3.15 (m, 1H), 2.35-2.33 (m, 1H), 1.89-1.83 (m, 2H), 1.62-1.40 (m, 6H), 1.16-1.11 (m, 4H). LCMS (ESI): m / z 503.0 (M + H) ^<+> .
(Example 11-7)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [ d] thiazole-6-carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxy according to general procedure 1D Starting from cyclohexyl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-5), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2 -(Difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-7 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.36 (br s, 1H), 8.55 (d, J = 1.0 Hz, 1H), 7.77-7.74 (m, 1H), 7.62-7.54 (m 2H ), 7.40-7.09 (m, 3H), 6.33 (br s, 1H), 4.37 (s, 2H), 3.35-3.30 (m, 1H), 2.35-2.30 (m, 1H), 1.94-1.71 (m, 6H), 1.54-1.47 (m, 2H), 1.14-1.09 (m, 4H). LCMS (ESI): m / z 575.1 (M + H) ⁺ .
(Example 11-8)
2- (4-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -3-fluorophenyl ) Acetic acid

Example 2- (4-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- according to general procedure 1D Starting from hydroxycyclohexyl) -3-fluorophenyl) acetonitrile 12-1, the title compound 2- (4-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl)) Isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -3-fluorophenyl) acetic acid 11-8 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 7.65-7.45 (m, 4H), 6.99-6.93 (m, 2H), 4.93 (br s, 1H), 4.30 (s, 2H), 3.43 ( s, 2H), 3.17-3.13 (m, 1H), 2.36-2.33 (m, 1H), 1.88-1.83 (m, 2H), 1.54-1.45 (m, 6H), 1.17-1.09 (m, 4H), The CO ₂ H proton is not split. LC / MS (ESI): m / z 533.7 (M + H) ^<+> .
(Example 11-9)
2- (3-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorophenyl ) Acetic acid

Example 2- (3-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- following general procedure 1D Starting from hydroxycyclohexyl) -4-fluorophenyl) acetonitrile 12-2, the title compound 2- (3-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl)) Isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorophenyl) acetic acid 11-9 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 7.44-7.41 (m, 3H), 7.34-7.31 (m, 1H), 7.10-7.09 (m, 1H), 6.96-6.92 (m, 1H) , 4.35 (s, 2H), 3.55 (s, 2H), 3.28-3.24 (m, 1H), 2.23-2.16 (m, 1H), 2.02-1.97 (m, 2H), 1.71-1.69 (m, 4H) , 1.63-1.59 (m, 2H), 1.29-1.26 (m, 2H), 1.14-1.10 (m, 2H), CO ₂ H and hydroxyl protons are not resolved. LC / MS (ESI): m / z 534.0 (M + H) ^<+> .
(Example 11-10)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole- 6-carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxy according to general procedure 1D Starting from cyclohexyl) benzo [d] thiazole-6-carbonitrile (9-8), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) ) Phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-10 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.04 (br s, 1H), 8.68 (d, J = 1.5 Hz, 1H), 8.03-7.97 (m, 2H), 7.63-7.54 (m, 2H), 7.41-7.09 (m, 3H), 6.25 (br s, 1H), 4.38 (s, 2H), 3.33-3.28 (m, 1H), 2.35-2.31 (m, 1H), 1.94-1.48 (m , 8H), 1.15-1.09 (m, 4H). LCMS (ESI): m / z 557.0 (M + H) ⁺ .
(Example 11-11)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6 carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (2-cyclopropylphenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) according to general procedure 1D Starting from benzo [d] thiazole-6-carbonitrile (9-9), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2-cyclopropylphenyl) iso) Oxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-11 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.10 (br s, 1H), 8.68 (d, J = 1.0 Hz, 1H), 8.03-7.97 (m, 2H), 7.41-7.38 (m, 1H), 7.30-7.24 (m, 2H), 6.98 (d, J = 8.0 Hz, 1H), 6.21 (br s, 1H), 4.32 (s, 2H), 3.32-3.26 (m, 1H), 2.35- 2.30 (m, 1H), 1.90-1.69 (m, 7H), 1.58-1.50 (m, 2H), 1.15-1.09 (m, 4H), 0.88-0.87 (m, 2H), 0.71-0.69 (m, 2H LCMS (ESI): m / z 531.1 (M + H) ⁺ .
(Examples 11-12)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6 -Carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dimethylphenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl according to general procedure 1D ) Starting from benzo [d] thiazole-6-carbonitrile (9-10), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dimethylphenyl) ) Isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-12 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.12 (br s, 1H), 8.69 (s, 1H), 8.03-7.97 (m, 2H), 7.29 (t, J = 7.5 Hz, 1H) , 7.17-7.16 (m, 2H), 6.15 (br s, 1H), 4.15 (s, 2H), 3.27-3.19 (m, 1H), 2.35-2.32 (m, 1H), 2.05 (s, 6H), 1.94-1.69 (m, 6H), 1.54-1.48 (m, 2H), 1.18-1.08 (m, 4H). LCMS (ESI): m / z 519.1 (M + H) ⁺ .
(Examples 11-13)
2-((1s, 4s) -4-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole- 6-carboxylic acid

Example 2-((1s, 4s) -4-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -1-hydroxy according to general procedure 1D Starting from cyclohexyl) benzo [d] thiazole-6-carbonitrile (9-11), the title compound 2-((1s, 4s) -4-((4-cyclopropyl-1- (2,6-dichlorophenyl) ) -1H-pyrazol-5-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-13 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.09 (s, 1H), 8.68 (d, J = 1.5 Hz, 1H), 8.02-7.96 (m, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.62-7.58 (m, 1H), 7.44 (s, 1H), 6.21 (s, 1H), 4.43 (s, 2H), 3.23-3.21 (m, 1H), 1.89-1.79 (m, 5H), 1.71-1.69 (m, 2H), 1.46-1.41 (m, 2H), 0.93-0.89 (m, 2H), 0.65-0.62 (m, 2H). LCMS (ESI): m / z 558.0 ( M + 1) ⁺ .
(Examples 11-14)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole -6-carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1- following general procedure 1D Starting from hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-12), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (tri Fluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-14 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.07 (br s, 1H), 8.68 (d, J = 1.0 Hz, 1H), 8.03-7.97 (m, 2H), 7.70-7.66 (m, 2H), 7.58-7.55 (m, 2H), 6.20 (br s, 1H), 4.37 (s, 2H), 3.35-3.31 (m, 1H), 2.36-2.33 (m, 1H), 1.95-1.73 (m , 6H), 1.57-1.49 (m, 2H), 1.16-1.09 (m, 4H). LCMS (ESI): m / z 575.0 (M + 1) ⁺ .
(Examples 11-15)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole- 6-carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethyl) phenyl) isoxazol-4-yl) methoxy) -1-hydroxy according to general procedure 1D Starting from cyclohexyl) benzo [d] thiazole-6-carbonitrile (9-13), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethyl) ) Phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-15 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 8.69 (d, J = 1.5 Hz, 1H), 8.03-7.97 (m, 2H), 7.84-7.82 (m, 1H), 7.74-7.65 (m , 3H), 6.97 (t, J = 54.8 Hz, 1H), 4.33 (s, 2H), 3.40-3.37 (m, 1H), 2.36-2.35 (m, 1H), 1.98-1.79 (m, 6H), 1.62-1.55 (m, 2H), 1.17-1.12 (m, 4H), CO ₂ H and hydroxyl protons are not resolved. LCMS (ESI): m / z 541.0 (M + 1) ^<+> .
(Examples 11-16)
2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d ] Thiazole-6-carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy)-according to general procedure 1D Starting from 1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-14), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (3 5-Dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-16 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.12 (br s, 1H), 8.86 (s, 2H), 8.69 (d, J = 1.0 Hz, 1H), 8.03-7.97 (m, 2H) , 6.16 (br s, 1H), 4.39 (s, 2H), 3.28-3.26 (m, 1H), 2.40-2.36 (m, 1H), 1.92-1.79 (m, 4H), 1.68-1.66 (m, 2H ), 1.45-1.38 (m, 2H), 1.20-1.11 (m, 4H). LCMS (ESI): m / z 560.0 (M + 1) ⁺ .
(Examples 11-17)
2-((1s, 4s) -4-((4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazol-5-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] Thiazole-6-carboxylic acid

Example 2-((1s, 4s) -4-((4-cyclopropyl-1- (2- (difluoromethoxy) phenyl) -1H-pyrazol-5-yl) methoxy) -1 according to general procedure 1D Starting from -hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-15), the title compound 2-((1s, 4s) -4-((4-cyclopropyl-1- (2- ( Difluoromethoxy) phenyl) -1H-pyrazol-5-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-17 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.16 (br s, 1H), 8.68 (d, J = 1.0 Hz, 1H), 8.03-7.97 (m, 2H), 7.61-7.57 (m, 1H), 7.53-7.51 (m, 1H), 7.43-7.38 (m, 3H), 7.12 (t, J = 73.8 Hz, 1H), 6.22 (br s, 1H), 4.46 (s, 2H), 3.26- 3.23 (m, 1H), 1.91-1.78 (m, 5H), 1.70-1.68 (m, 2H), 1.51-1.46 (m, 2H), 0.91-0.89 (m, 2H), 0.63-0.62 (m, 2H LCMS (ESI): m / z 556.1 (M + 1) ⁺ .
(Examples 11-18)
2-((1s, 4s) -4-((3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropylisoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d ] Thiazole-6-carboxylic acid

Example 2-((1s, 4s) -4-((3- (2,6-bis (difluoromethyl) phenyl) -5-cyclopropylisoxazol-4-yl) methoxy)-following the general procedure 1D Starting from 1-hydroxycyclohexyl) benzo [d] thiazole-6-carbonitrile (9-16), the title compound 2-((1s, 4s) -4-((3- (2,6-bis (difluoro Methyl) phenyl) -5-cyclopropylisoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid 11-18 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.11 (br s, 1H), 8.68 (d, J = 1.5 Hz, 1H), 8.02-7.89 (m, 5H), 6.70 (t, J = 54.0 Hz, 2H), 6.15 (br s, 1H), 4.23 (s, 2H), 3.28-3.24 (m, 1H), 2.37-2.32 (m, 1H), 1.92-1.64 (m, 6H), 1.45- 1.37 (m, 2H), 1.20-1.13 (m, 4H). LCMS (ESI): m / z 591.2 (M + 1) ⁺ .
(Examples 11-19)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5-fluorobenzo [ d] thiazole-6-carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxy according to general procedure 1D Starting from cyclohexyl) -5-fluorobenzo [d] thiazole-6-carbonitrile (8-3), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2 -(Difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5-fluorobenzo [d] thiazole-6-carboxylic acid 11-19 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.36 (br s, 1H), 8.63 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 14.5 Hz, 1H), 7.63-7.53 (m, 2H), 7.42-7.05 (m, 3H), 6.26 (br s, 1H), 4.37 (s, 2H), 3.30-3.27 (m, 1H), 2.35-2.31 (m, 1H), 1.92- 1.70 (m, 6H), 1.54-1.48 (m, 2H), 1.16-1.06 (m, 4H). LC / MS (ESI): m / z 575.2 (M + H) ⁺ .
(Examples 11-20)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5-fluorobenzo [d] Thiazole-6-carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) according to general procedure 1D Starting from -5-fluorobenzo [d] thiazole-6-carbonitrile (8-4), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6 -Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5-fluorobenzo [d] thiazole-6-carboxylic acid 11-20 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 8.32 (d, J = 6.5 Hz, 1H), 7.66-7.56 (m, 4H), 6.14 (br s, 1H), 4.31 (s, 2H) , 3.25-3.19 (m, 1H), 2.38-2.33 (m, 1H), 1.88-1.77 (m, 4H), 1.68-1.65 (m, 2H), 1.48-1.40 (m, 2H), 1.18-1.10 ( m, 4H), CO ₂ H protons are not resolved. LC / MS (ESI): m / z 577.1 (M + H) ^<+> .
(Example 11-21)
2-((1s, 3s) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclobutyl) -4-fluorobenzo [d ] Thiazole-6-carboxylic acid

Example 2-((1s, 3s) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclobutyl according to general procedure 1D ) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-19) starting from the title compound 2-((1s, 3s) -3-((5-cyclopropyl-3- (2, 6-Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclobutyl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-21 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.36 (br s, 1H), 8.55 (s, 1H), 7.78 (d, J = 11.5 Hz, 1H), 7.64-7.56 (m, 3H) , 7.00 (br s, 1H), 4.23 (s, 2H), 4.14-4.09 (m, 1H), 2.79-2.75 (m, 2H), 2.41-2.36 (m, 1H), 2.23-2.19 (m, 2H ), 1.19-1.11 (m, 4H). LC / MS (ESI): m / z 548.9 (M + H) ⁺ .
(Examples 11-22)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) benzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8 according to general procedure 1D Starting from -hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole-6-carbonitrile (8-5), the title compound 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] Thiazole-6-carboxylic acid 11-22 was synthesized. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 13.10 (br s, 1H), 8.69 (s, 1H), 8.10-8.06 (m, 2H), 7.70-7.63 (m, 2H), 7.60- 7.54 (m, 1H), 6.41 (s, 1H), 4.29 (s, 2H), 3.53-3.47 (m, 1H), 2.37-2.33 (m, 3H), 1.86-1.74 (m, 4H), 1.65- 1.58 (m, 2H), 1.45-1.39 (m, 2H), 1.21-1.10 (m, 4H). LC / MS (ESI): m / z 584.9 (M + H) ⁺ .
(Examples 11-23)
2-((1R, 3r, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) benzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 3r, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8 according to general procedure 1D Starting from -hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole-6-carbonitrile (8-6), the title compound 2-((1R, 3r, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] Thiazole-6-carboxylic acid 11-23 was synthesized. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 13.10 (s, 1H), 8.68 (s, 1H), 8.11-7.99 (m, 2H), 7.65-7.60 (m, 2H), 7.57-7.50 (m, 1H), 6.31 (s, 1H), 4.26 (s, 2H), 3.50-3.46 (m, 1H), 2.38-2.32 (m, 1H), 2.25-2.14 (m, 4H), 1.62-1.57 (m, 2H), 1.55-1.48 (m, 4H), 1.19-1.05 (m, 4H). LC / MS (ESI): m / z 584.9 (M + H) ^<+> .
(Examples 11-24)
4-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) -3-fluorobenzoic acid

Example 4-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8 according to general procedure 1D Starting from -hydroxybicyclo [3.2.1] octane-8-yl) -3-fluorobenzonitrile (8-7), the title compound 4-((1R, 3s, 5S, 8r) -3- ( (5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -3-fluorobenzoic acid (11 -24) was synthesized. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.82 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 12.8 Hz, 1H), 7.45-7.30 (m, 4H), 4.35 (s, 2H), 3.62-3.56 (m, 1H), 2.63 (s, 2H), 2.23-2.18 (m, 1H), 1.97 (t, J = 10.8 Hz, 2H), 1.78-1.71 (m, 2H), 1.55 -1.44 (m, 4H), 1.32-1.24 (m, 2H), 1.17-1.08 (m, 2H). Carboxylate and hydroxyl protons are not resolved. ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-110.02. LC / MS (ESI): m / z 544.0 (M−H) ⁻ .
(Examples 11-25)
3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) benzoic acid

Example 3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8 according to general procedure 1D Starting from -hydroxybicyclo [3.2.1] octane-8-yl) benzonitrile (8-8), the title compound 3-((1R, 3s, 5S, 8r) -3-((5-cyclo Propyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzoic acid (11-25) was synthesized. ¹ H-NMR (400 MHz, DMSO): δ 12.91 (br s, 1H), 8.03 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.70-7.63 (m, 3H), 7.60- 7.55 (m, 1H), 7.41 (t, J = 7.6 Hz, 1H), 5.12 (s, 1H), 4.28 (s, 2H), 3.50-3.42 (m, 1H), 2.39-2.34 (m, 3H) , 1.85 (t, J = 10.8 Hz, 2H), 1.61-1.54 (m, 2H), 1.32-1.22 (m, 4H), 1.17-1.09 (m, 4H). LC / MS (ESI): m / z 525 .9 (M−H) ⁻ .
(Examples 11-26)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) isonicotinic acid

Example 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8 according to general procedure 1D Starting from -hydroxybicyclo [3.2.1] octane-8-yl) isonicotinonitrile (15-5), the title compound 2-((1R, 3s, 5S, 8r) -3-((5 -Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) isonicotinic acid (11-26) did. ¹ H-NMR (400 MHz, DMSO): δ 13.75 (br s, 1H), 8.61 (d, J = 4.8 Hz, 1H), 7.97 (s, 1H), 7.68-7.63 (m, 3H), 7.57 ( dd, J = 9.2, 6.8 Hz, 1H), 5.33 (s, 1H), 4.28 (s, 2H), 3.50-3.42 (m, 1H), 2.39-2.34 (m, 1H), 1.84 (t, J = 10.8 Hz, 2H), 1.60-1.54 (m, 2H), 1.34-1.23 (m, 5H), 1.17-1.08 (m, 5H). LC / MS (ESI): m / z 529.0 (M + H) ⁺ .
(Examples 11-27)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8 according to general procedure 1D Starting from -hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (8-9), the title compound 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-Fluorobenzo [d] thiazole-6-carboxylic acid (11-27) was synthesized. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 13.36 (br s, 1H), 8.55 (s, 1H), 7.75 (d, J = 10.8 Hz, 1H), 7.67-7.60 (m, 2H) , 7.59-7.55 (m, 1H), 6.51 (br s, 1H), 4.29 (s, 2H), 3.53-3.34 (m, 1H), 2.39-2.33 (m, 3H), 1.88-1.78 (m, 4H ), 1.65-1.59 (m, 2H), 1.48-1.39 (m, 2H), 1.25-1.08 (m, 4H). ¹⁹ F-NMR (376 MHz, DMSO-d ₆ ): δ -122.37.LC/MS (ESI): m / z 603.2 (M + H) ⁺ .
(Examples 11-28)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3. 2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Following general procedure 1D, 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8 Starting from -hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (8-10), the title compound 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8- Yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid (11-28) was synthesized. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 13.35 (br s, 1H), 8.55 (s, 1H), 7.75 (d, J = 11.2 Hz, 1H), 7.61 (t, J = 8.0 Hz , 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.42-7.35 (m, 2H), 7.22 (t, J = 73.6 Hz, 1H), 6.52 (br s, 1H), 4.35 (s, 2H ), 3.62-3.52 (m, 1H), 2.45-2.25 (m, 3H), 1.93-1.75 (m, 4H), 1.73-1.57 (m, 2H), 1.45-1.38 (m, 2H), 1.19-1.04 (m, 4H). ¹⁹ F-NMR (376 MHz, DMSO-d ₆ ): δ −122.36, −82.04. LC / MS (ESI): m / z 601.2 (M ⁺ H) ⁺ .
(Examples 11-29)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Following general procedure 1D, 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy ) -8-Hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (8-11) starting from the title compound 2-((1R , 3s, 5S, 8r) -3-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid (11-29) was synthesized. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 13.35 (br s, 1H), 8.84 (s, 2H), 8.54 (s, 1H), 7.65 (d, J = 10.8 Hz, 1H), 6.49 (s, 1H), 4.35 (s, 2H), 3.55-3.51 (m, 1H), 2.44-2.33 (m, 3H), 1.83-1.72 (m, 4H), 1.63-1.56 (m, 2H), 1.48 -1.41 (m, 2H), 1.20-1.08 (m, 4H). ¹⁹ F-NMR (376 MHz, DMSO-d ₆ ): δ -122.42. LC / MS (ESI): m / z 604.2 (M + H) ⁺ .
(Example 11-30)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6 carboxylic acid

Following general procedure 1D, 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [ d] Starting from thiazole-6-carbonitrile (8-12), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole- 4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-6-carboxylic acid (11-30) was synthesized. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 13.07 (br s, 1H), 8.67 (s, 1H), 8.02-7.96 (m, 2H), 7.66-7.56 (m, 3H), 6.19 ( s, 1H), 4.31 (s, 2H), 3.25-3.22 (m, 1H), 2.36-2.32 (m, 1H), 1.87-1.81 (m, 4H), 1.68-1.66 (m, 2H), 1.48- 1.43 (m, 2H), 1.16-1.11 (m, 4H). LC / MS (ESI): m / z 558.7 (M + H) ⁺ .
(Example 11-31)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [d] Thiazole-6-carboxylic acid

2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4 according to general procedure 1D Starting from -fluorobenzo [d] thiazole-6-carbonitrile (8-13), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) ) Isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carboxylic acid (11-31) was synthesized. ¹ H-NMR (400 MHz, DMSO): δ 13.34 (br s, 1H), 8.54 (s, 1H), 7.76-7.56 (m, 4H), 6.30 (s, 1H), 4.32 (s, 2H), 3.27-3.25 (m, 1H), 2.37-2.33 (m, 1H), 1.88-1.79 (m, 4H), 1.70-1.67 (m, 2H), 1.45-1.42 (m, 2H), 1.16-1.09 (m , 4H). LC / MS (ESI): m / z 577.4 (M + H) ⁺ .
(Examples 11-32)
2-((1R, 4S) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxy-2,2-dimethylcyclohexyl) -4 -Fluorobenzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 4S) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxy-2 according to general procedure 1D , 2-Dimethylcyclohexyl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-18), starting from racemic title compound 2-((1R, 4S) -4-((5- Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxy-2,2-dimethylcyclohexyl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-32 Was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.35 (br s, 1H), 8.54 (d, J = 1.5 Hz, 1H), 7.74 (dd, J = 14.0 Hz, J = 2.0 Hz, 1H ), 7.67-7.57 (m, 3H), 6.23 (br s, 1H), 4.31 (q, J = 16.0 Hz, 2H), 3.47-3.41 (m, 1H), 2.39-2.34 (m, 2H), 1.78 -1.70 (m, 2H), 1.55-1.33 (m, 3H), 1.23-1.09 (m, 4H), 0.90 (s, 3H), 0.80 (s, 3H). LC / MS (ESI): m / z 605 .2 (M + H) ⁺ .
(Examples 11-33)
2-((1S, 4R) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxy-3,3-dimethylcyclohexyl) -4 -Fluorobenzo [d] thiazole-6-carboxylic acid

Example 2-((1S, 4R) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxy-3 according to general procedure 1D , 3-Dimethylcyclohexyl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-19) starting from racemic title compound 2-((1S, 4R) -4-((5- Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxy-3,3-dimethylcyclohexyl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-33 Was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.35 (br s, 1H), 8.55 (s, J = 1.5 Hz, 1H), 7.75 (dd, J = 14.0 Hz, J = 1.5 Hz, 1H ), 7.66-7.55 (m, 3H), 6.21 (br s, 1H), 4.50 (d, J = 14.5 Hz, 1H), 4.15 (d, J = 14.5 Hz, 1H), 3.07-3.04 (m, 1H ), 2.37-2.33 (m, 1H), 1.93-1.84 (m, 3H), 1.70-1.63 (m, 2H), 1.53-1.49 (m, 1H), 1.18-1.11 (m, 4H), 0.90 (s , 3H), 0.65 (s, 3H). LC / MS (ESI): m / z 605.1 (M + H) ⁺ .
(Examples 11-34)
2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4- Fluorobenzo [d] thiazole-6-carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy)-according to general procedure 1D Starting from 1-hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-20), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3 -(3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-34 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.46 (br s, 1H), 8.89 (s, 2H), 8.59 (s, 1H), 7.80 (d, J = 11.5 Hz, 1H), 6.37 (br s, 1H), 4.43 (s, 2H), 3.35-3.31 (m, 1H), 2.44-2.41 (m, 1H), 1.97-1.71 (m, 6H), 1.48-1.40 (m, 2H), 1.24-1.15 (m, 4H). LCMS (ESI): m / z 578.0 (M + H) ⁺ .
(Examples 11-35)
2-((1R, 2r, 3S, 5s, 7s) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyadamantane-2- Yl) benzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 2r, 3S, 5s, 7s) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) according to general procedure 1D Starting from 2-hydroxyadamantan-2-yl) benzo [d] thiazole-6-carbonitrile (8-14), the title compound 2-((1R, 2r, 3S, 5s, 7s) -5- ( (5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyadamantan-2-yl) benzo [d] thiazole-6-carboxylic acid 11-35 was synthesized. . ¹ H-NMR (400 MHz, DMSO): δ 13.13 (br s, 1H), 8.69 (s, 1H), 8.05-8.00 (m, 2H), 7.64-7.54 (m, 3H), 6.10 (br s, 1H), 4.24 (s, 2H), 2.42-2.28 (m, 3H), 2.18-2.15 (m, 2H), 1.94-1.87 (m, 3H), 1.49-1.08 (m, 10H) .MS (ESI) : M / z 611.2 (M + 1) ⁺ .
(Examples 11-36)
2-((1R, 2s, 3S, 5s, 7s) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyadamantane-2- Yl) benzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 2s, 3S, 5s, 7s) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) according to general procedure 1D Starting from 2-hydroxyadamantan-2-yl) benzo [d] thiazole-6-carbonitrile (8-15), the title compound 2-((1R, 2s, 3S, 5s, 7s) -5- ( (5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyadamantan-2-yl) benzo [d] thiazole-6-carboxylic acid 11-36 was synthesized. . ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.71 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.92 (t, J = 8.4 Hz, 1H), 5.98 (s, 1H), 4.15 (s, 2H), 2.42-2.36 (m, 2H), 2.23-2.15 (m, 3H ), 2.03-1.98 (m, 1H), 1.55-1.40 (m, 6H), 1.38-1.30 (m, 2H), 1.08-0.96 (m, 4H), CO ₂ H protons are not split. MS (ESI): m / z 611.2 (M + 1) ^<+> .
(Examples 11-37)
2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1 ] Octane-8-yl) benzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) -8- according to general procedure 1D Starting from hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole-6-carbonitrile (15-11), the title compound 2-((1R, 3s, 5S, 8r)- 3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole- 6-carboxylic acid 11-37 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.16 (br s, 1H), 8.69 (s, 1H), 8.03-7.99 (m, 2H), 7.67-7.57 (m, 3H), 6.42 ( br s, 1H), 4.23 (s, 2H), 3.51-3.45 (m, 1H), 2.54 (s, 3H), 2.36 (s, 2H), 1.84-1.75 (m, 4H), 1.61-1.57 (m , 2H), 1.44-1.38 (m, 2H). LCMS (ESI): m / z 559.0 (M + H) ⁺ .
(Examples 11-38)
2-((1R, 3r, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1 ] Octane-8-yl) benzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 3r, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) -8- according to general procedure 1D Starting from hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole-6-carbonitrile (15-12), the title compound 2-((1R, 3r, 5S, 8r)- 3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole- 6-carboxylic acid 11-38 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.13 (br s, 1H), 8.68 (s, 1H), 8.02 (s, 2H), 7.64-7.53 (m, 3H), 6.31 (br s , 1H), 4.21 (s, 2H), 3.57 (1H, hidden in solvent signal), 2.53-2.51 (m, 3H), 2.25-2.17 (m, 4H), 1.60-1.50 (m, 6H). LCMS (ESI): m / z 559.1 (M + H) ^<+> .
(Examples 11-39)
2-((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy-3-methylbicyclo [3. 2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy according to general procedure 1D Starting from -3-methylbicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile 15-13, the title compound 2-((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy-3-methylbicyclo [3.2.1] octane-8- Yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-39 was synthesized as a single isomer. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.40 (br s, 1H), 8.55 (d, J = 1.5 Hz, 1H), 7.76 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H ), 7.63-7.52 (m, 3H), 6.44 (br s, 1H), 4.22 (s, 2H), 2.32-2.27 (m, 3H), 2.01-1.98 (m, 2H), 1.70-1.42 (m, 6H), 1.16-1.06 (m, 4H), 0.91 (s, 3H). LCMS (ESI): m / z 617.1 (M + H) ⁺ .
(Example 11-40)
2-((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3- (difluoromethyl) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Following general procedure 1D, Example 2-((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3- ( Starting from difluoromethyl) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile 15-14, the title compound 2-((1R , 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3- (difluoromethyl) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-40 was synthesized as a single isomer. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.39 (br s, 1H), 8.57 (d, J = 1.5 Hz, 1H), 7.77 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H ), 7.62-7.51 (m, 3H), 6.55 (br s, 1H), 5.78 (t, J = 55.3 Hz, 1H), 4.45 (s, 2H), 2.39-2.31 (m, 3H), 2.19-2.17 (m, 2H), 1.73-1.70 (m, 2H), 1.48 (s, 4H), 1.18-1.06 (m, 4H). LCMS (ESI): m / z 653.1 (M + H) ⁺ .
(Example 11-41)
2-((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy-3- (methoxymethyl) bicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy according to general procedure 1D Starting from -3- (methoxymethyl) bicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile 15-15, the title compound 2-((1R , 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy-3- (methoxymethyl) bicyclo [3.2. 1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-41 was synthesized as a single isomer. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.39 (br s, 1H), 8.55 (d, J = 1.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, J = 1.5 Hz, 1H ), 7.62-7.52 (m, 3H), 6.40 (br s, 1H), 4.30 (s, 2H), 3.15 (s, 3H), 3.10 (s, 2H), 2.34-2.30 (m, 3H), 2.00 -1.97 (m, 2H), 1.69-1.66 (m, 2H), 1.53-1.44 (m, 4H), 1.15-1.09 (m, 4H). LCMS (ESI): m / z 647.1 (M + H) ⁺ .
(Examples 11-42)
6-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -1-methyl-1H-indole -3-carboxylic acid

Example 6-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) according to general procedure 1D Starting from -1-methyl-1H-indole-3-carbonitrile (9-21), the title compound 6-((1s, 4s) -4-((5-cyclopropyl-3- (2,6- Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -1-methyl-1H-indole-3-carboxylic acid 11-42 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 11.89 (br s, 1H), 7.98 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.68-7.65 (m, 2H) , 7.60-7.55 (m, 2H), 7.29 (d, J = 8.5 Hz, 1H), 4.77 (s, 1H), 4.32 (s, 2H), 3.82 (s, 3H), 3.23-3.19 (m, 1H ), 2.38-2.33 (m, 1H), 1.75-1.70 (m, 2H), 1.63-1.48 (m, 6H), 1.18-1.10 (m, 4H). LCMS (ESI): m / z 555.0 (M + H ) ⁺ .
(Examples 11-43)
7-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-3-carboxylic acid

Example 7-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) according to general procedure 1D Starting from quinoline-3-carbonitrile (9-22), the title compound 7-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4- Yl) methoxy) -1-hydroxycyclohexyl) quinoline-3-carboxylic acid 11-43 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.48 (br s, 1H), 9.29 (d, J = 2.5 Hz, 1H), 8.93 (d, 1H, J = 1.5 Hz), 8.15-8.10 (m, 2H), 7.81-7.78 (m, 1H), 7.67-7.66 (m, 2H), 7.60-7.57 (m, 1H), 4.33 (s, 2H), 3.29-3.25 (m, 1H), 2.38 -2.35 (m, 1H), 1.83-1.78 (m, 2H), 1.67-1.50 (m, 6H), 1.19-1.11 (m, 4H). LCMS (ESI): m / z 553.0 (M + H) ⁺ .
(Examples 11-44)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-5-carboxylic acid

Example 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) according to general procedure 1D Starting from quinoline-5-carbonitrile (9-23), the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4- Yl) methoxy) -1-hydroxycyclohexyl) quinoline-5-carboxylic acid 11-44 was synthesized. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 9.86 (d, J = 9.0 Hz, 1H), 8.85 (d, J = 8.5 Hz, 1H), 8.50 (d, J = 7.5 Hz, 1H), 8.03 -7.98 (m, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.45-7.42 (m, 2H), 7.38-7.33 (m, 1H), 4.41 (s, 2H), 3.39-3.35 (m , 1H), 2.24-2.19 (m, 1H), 2.03-1.98 (m, 2H), 1.90-1.79 (m, 6H), 1.30-1.25 (m, 2H), 1.17-1.10 (m, 2H), hydroxyl And carboxylate protons are not resolved. LCMS (ESI): m / z 553.2 (M + H) ^<+> .
(Examples 11-45)
6-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -1-isopropyl-1H-indazole -3-carboxylic acid

Example 6-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) according to general procedure 1D Starting from -1-isopropyl-1H-indazole-3-carbonitrile (9-24), the title compound 6-((1s, 4s) -4-((5-cyclopropyl-3- (2,6- Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -1-isopropyl-1H-indazole-3-carboxylic acid 11-45 was synthesized. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.08 (d, J = 8.5 Hz, 1H), 7.54 (s, 1H), 7.41-7.39 (m, 2H), 7.34-7.30 (m, 1H), 7.18 (d, J = 8.5 Hz, 1H), 4.78-4.75 (m, 1H), 4.37 (s, 2H), 3.27-3.25 (m, 1H), 2.21-2.18 (m, 1H), 1.79-1.62 ( m, 8H), 1.48 (d, J = 6.5 Hz, 6H), 1.28-1.25 (m, 2H), 1.14-1.10 (m, 2H), hydroxyl and carboxylate protons are not resolved. LCMS (ESI): m / z 584.1 (M + H) ^<+> .
(Example 11-46)
2-((3aR, 6aS) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyoctahydropentalen-2-yl)- 4-Fluorobenzo [d] thiazole-6-carboxylic acid

Example 2-((3aR, 6aS) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyoctahydro according to general procedure 1D Starting from pentalen-2-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-25), the title compound 2-((3aR, 6aS) -5-((5-cyclopropyl -3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyoctahydropentalen-2-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-46 Synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.33 (br s, 1H), 8.55 (s, 1H), 7.75 (d, 1H, J = 11.0 Hz), 7.67-7.65 (m, 2H) , 7.60-7.57 (m, 1H), 6.36 (br s, 1H), 4.25 (s, 2H), 3.66-3.62 (m, 1H), 2.58-2.57 (m, 2H), 2.37-2.31 (m, 3H ), 1.95-1.89 (m, 4H), 1.54-1.49 (m, 2H), 1.17-1.11 (m, 4H). LC / MS (ESI): m / z 603.0 (M + H) ⁺ .
(Examples 11 to 47)
4-((3aR, 6aS) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyoctahydropentalen-2-yl)- 3-Fluorobenzoic acid

Example 4-((3aR, 6aS) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyoctahydro according to general procedure 1D Starting from pentalen-2-yl) -3-fluorobenzonitrile (9-26), the title compound 4-((3aR, 6aS) -5-((5-cyclopropyl-3- (2,6- Dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxyoctahydropentalen-2-yl) -3-fluorobenzoic acid 11-47 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.15 (br s, 1H), 7.73-7.71 (m, 1H), 7.72-7.53 (m, 5H), 4.23 (s, 2H), 3.61- 3.57 (m, 1H), 2.40-2.30 (m, 3H), 2.25-2.20 (m, 2H), 1.91-1.79 (m, 4H), 1.61-1.55 (m, 2H), 1.16-1.10 (m, 4H ), Hydroxyl protons are not resolved. LC / MS (ESI): m / z 546.0 (M + H) ^<+> .
(Examples 11-48)
2-((1R, 2S, 4R) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxybicyclo [2.2.1] Heptan-2-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 2S, 4R) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxy according to general procedure 1D Starting from bicyclo [2.2.1] heptan-2-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (major isomer 9-27), the title compound 2-((1R, 2S , 4R) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxybicyclo [2.2.1] heptan-2-yl)- 4-Fluorobenzo [d] thiazole-6-carboxylic acid 11-48 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.35 (br s, 1H), 8.53 (d, J = 1.5 Hz, 1H), 7.75 (dd, J = 11.0 Hz, J = 1.5 Hz, 1H ), 7.67-7.65 (m, 2H), 7.60-7.57 (m, 1H), 6.50 (br s, 1H), 4.27-4.20 (m, 2H), 3.76-3.74 (m, 1H), 2.40-2.38 ( m, 1H), 2.25-2.09 (m, 4H), 1.89-1.80 (m, 2H), 1.58-1.56 (m, 1H), 1.25-1.23 (m, 1H), 1.18-1.11 (m, 4H). LC / MS (ESI): m / z 589.1 (M + H) ^<+> .
(Examples 11-49)
2-((1R, 2S, 4R) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxybicyclo [2.2.1] Heptan-2-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 2S, 4R) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxy according to general procedure 1D Starting from bicyclo [2.2.1] heptan-2-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (minor isomer 10-27), the title compound 2-((1R, 2S , 4R) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -2-hydroxybicyclo [2.2.1] heptan-2-yl)- 4-Fluorobenzo [d] thiazole-6-carboxylic acid 11-49 was synthesized. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 13.38 (br s, 1H), 8.53 (d, J = 1.0 Hz, 1H), 7.75 (dd, J = 11.5 Hz, J = 1.0 Hz, 1H) , 7.65-7.64 (m, 2H), 7.58-7.55 (m, 1H), 6.53 (br s, 1H), 4.30-4.23 (m, 2H), 3.46-3.45 (m, 1H), 2.43-2.30 (m , 3H), 2.16 (brs, 2H), 1.90-1.88 (m, 1H), 1.23-1.09 (m, 6H), 0.90-0.88 (m, 1H). LC / MS (ESI): m / z 589. 1 (M + H) ⁺ .
(Example 11-50)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [ 3.2.1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) isoxazol-4-yl) according to general procedure 1D Starting from methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (15-23), the title compound 2-(( 1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-50 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.41 (br s, 1H), 8.57 (d, J = 1.5 Hz, 1H), 7.78 (dd, J = 11.0 Hz, J = 1.5 Hz, 1H ), 7.07-6.95 (m, 3H), 6.61 (br s, 1H), 4.85 (s, 2H), 4.48 (s, 2H), 3.81-3.76 (m, 1H), 2.45 (s, 2H), 2.31 -2.27 (m, 1H), 2.24 (s, 6H), 2.02 (t, J = 11.0 Hz, 2H), 1.87-1.84 (m, 4H), 1.57-1.54 (m, 2H), 1.14-1.02 (s , 4H). LCMS (ESI): m / z 593.2 (M + H) ⁺ .
(Examples 11-51)
2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-isopropylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1 ] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Example 2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-isopropylisoxazol-4-yl) methoxy) -8- according to general procedure 1D Starting from hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (15-20), the title compound 2-((1R, 3s, 5S , 8r) -3-((3- (2,6-dichlorophenyl) -5-isopropylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4 -Fluorobenzo [d] thiazole-6-carboxylic acid 11-51 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.39 (br s, 1H), 8.56 (d, J = 1.5 Hz, 1H), 7.77-7.57 (m, 4H), 6.52 (br s, 1H ), 4.24 (s, 2H), 3.50-3.45 (m, 1H), 3.42-3.37 (m, 1H), 2.35 (s, 2H), 1.83-1.76 (m, 4H), 1.61-1.56 (m, 2H ), 1.43-1.40 (m, 2H), 1.35 (d, J = 6.5 Hz, 6H). LCMS (ESI): m / z 605.2 (M + H) ⁺ .
(Examples 11-52)
2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) isoxazol-4-yl) methoxy) -8 -Hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

According to general procedure 1D, Example 2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) isoxazole- 4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (15-21) starting from the title compound 2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) isoxazol-4-yl) methoxy) -8 -Hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-52 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.67 (br s, 1H), 8.56 (d, J = 1.0 Hz, 1H), 7.77-7.59 (dd, J = 11.0 Hz, J = 1.0 Hz , 1H), 7.69-7.59 (m, 3H), 6.46 (br s, 1H), 4.34 (s, 2H), 3.50-3.44 (m, 1H), 2.34 (s, 2H), 1.87 (s, 3H) , 1.83 (s, 3H), 1.80-1.72 (m, 4H), 1.57-1.52 (m, 2H), 1.45-1.38 (m, 2H). LCMS (ESI): m / z 623.0 (M + H) ⁺ .
(Example 11-53)
3- (3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3 2.1] octane-8-yl) phenyl) -2,2-dimethylpropanoic acid

Example 2- (3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) according to general procedure 1D ) -8-hydroxybicyclo [3.2.1] octane-8-yl) phenyl) -2-methylpropanenitrile (9-29) to give the title compound 3- (3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) Phenyl) -2,2-dimethylpropanoic acid 11-53 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 12.20 (br s, 1H), 7.67-7.57 (m, 3H), 7.29 (d, J = 8.0 Hz, 1H), 7.22-7.18 (m, 2H), 6.99 (d, J = 7.0 Hz, 1H), 4.28 (s, 2H), 3.47-3.43 (m, 1H), 2.78 (s, 2H), 2.38-2.34 (m, 3H), 1.87-1.83 (m, 2H), 1.57-1.52 (m, 2H), 1.29-1.10 (m, 8H), 1.05 (s, 6H), hydroxyl protons are not resolved. LCMS (ESI): m / z 605.3 (M + Na) ^<+> .
(Examples 11-54)
2-((1R, 5S) -8-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-hydroxybicyclo [3.2.1] octane- 3-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Following the general procedure 1D, Example 2-((1R, 5S) -8-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-hydroxybicyclo [ 3.2.1] Starting from octan-3-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile 40, the title compound 2-((1R, 5S) -8-((5-cyclo Propyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-hydroxybicyclo [3.2.1] octane-3-yl) -4-fluorobenzo [d] thiazole-6 Carboxylic acid 11-54 was synthesized as a single isomer. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.37 (br s, 1H), 8.54 (d, J = 1.5 Hz, 1H), 7.76 (dd, J = 1.5 Hz, J = 11.5 Hz, 1H ), 7.60-7.50 (m, 3H), 6.16 (br s, 1H), 4.34 (s, 2H), 3.43 (t, J = 4.5 Hz, 1H), 2.46-2.40 (m, 3H), 2.08-2.01 (m, 4H), 1.67-1.65 (m, 2H), 1.52-1.49 (m, 2H), 1.14-1.11 (m, 4H). LCMS (ESI): m / z 603.0 (M + H) ⁺ .
(Examples 11-55)
2-((1R, 5S) -8-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-hydroxybicyclo [3.2.1] octane- 3-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Following the general procedure 1D, Example 2-((1R, 5S) -8-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-hydroxybicyclo [ 3.2.1] Starting from octan-3-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile 41, the title compound 2-((1R, 5S) -8-((5-cyclo Propyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-hydroxybicyclo [3.2.1] octane-3-yl) -4-fluorobenzo [d] thiazole-6 Carboxylic acid 11-55 was synthesized as a single isomer. ¹ HNMR (500 MHz, DMSO-d ₆ ): δ 13.42 (br s, 1H), 8.57 (d, J = 1.0 Hz, 1H), 7.78 (dd, J = 1.5 Hz, J = 11.0 Hz, 1H), 7.66-7.56 (m, 3H), 5.90 (br s, 1H), 4.37 (s, 2H), 3.32 (t, J = 5.3 Hz, 1H), 2.45-2.39 (m, 3H), 2.15-2.01 (m , 4H), 1.27-1.14 (m, 8H). LC / MS (ESI): m / z 603.1 (M + H) ⁺ .
(Examples 11-56)
2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5- (2-hydroxypropan-2-yl) isoxazol-4-yl) methoxy) -8 -Hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

Following the general procedure 1D, Example 2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5- (2-hydroxypropan-2-yl) isoxazole- 4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (15-22) starting from the title compound 2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5- (2-hydroxypropan-2-yl) isoxazol-4-yl) methoxy) -8 -Hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-56 was synthesized. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.43 (br s, 1H), 8.53 (s, 1H), 7.75 (dd, J = 11.0 Hz, J = 0.7 Hz, 1H), 7.66-7.55 (m, 3H), 6.48 (s, 1H), 5.81 (s, 1H), 4.46 (s, 2H), 3.50-3.44 (m, 1H), 2.33 (s, 2H), 1.77-1.71 (s, 4H ), 1.58-1.53 (m, 8H), 1.42-1.39 (m, 2H). LCMS (ESI): m / z 603.1 (M−H ₂ O + H) ⁺ , 621.1 (M + H) ⁺ .
(Examples 11-57)
2- (3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclopentyl) benzo [d] thiazole-6-carboxylic acid

2- (3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclopentyl) benzo [d] thiazole-6-carbonitrile (8-17 , 35 mg, 0.07 mmol) and ethanol (1.5 mL) were treated with 4M NaOH (0.66 mL, 2.7 mmol) and the mixture was stirred at 85 ° C. overnight. The mixture was cooled to room temperature and concentrated under vacuum, then cooled in an ice bath, treated with water (2 mL) and the pH adjusted to about 4 with 1M HCl. The mixture was extracted twice with EtOAc (30 mL) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by chromatography (ISCO 4g GOLD silica, 0-100% EtOAc) gave the title compound 2- (3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy. ) -1-Hydroxycyclopentyl) benzo [d] thiazole-6-carboxylic acid. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 13.04 (s, 1H), 8.70-8.61 (m, 1H), 8.04-7.88 (m, 2H), 7.68-7.46 (m, 3H), 6.28 ( s, 1H), 4.32-4.12 (m, 2H), 4.10-3.89 (m, 1H), 2.48-2.27 (m, 2H), 2.06-1.91 (m, 3H), 1.86 (dd, J = 14.2, 4.4 Hz, 1H), 1.78-1.59 (m, 1H), 1.24-1.01 (m, 4H). MS (M + H): 544.9.
(Example 12-1)
2- (4-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -3-fluorophenyl Acetonitrile

Step 1: (1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- (2-fluoro-) in DCM (10 mL) To a solution of 4- (hydroxymethyl) phenyl) cyclohexanol (9-6) (250 mg, 0.50 mmol) was added MsCl (91 mg, 0.80 mmol) at 0 ° C. and the mixture was stirred at room temperature for 1 hour. Quench with water, extract 3 times with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to 4-((1s, 4s) -4-((5-cyclopropyl-3- (2,6- Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -3-fluorobenzylmethanesulfonate was produced.

Step 2: 4-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl in MeCN (8 mL) ) -3-fluorobenzyl methanesulfonate (238 mg, to a solution of 0.41 _mmol), was added _{K 2 CO 3 (113mg, 0.82mmol} ) and TMSCN (81mg, 0.82mmol). The mixture was stirred at 80 ° C. overnight, quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative TLC (PE / EtOAc = 4: 1) to give 2- (4-((1s, 4s) -4-((5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -3-fluorophenyl) acetonitrile 12-1 was obtained.

(Example 12-2)
2- (3-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorophenyl Acetonitrile

  (1s, 4s) -4-((5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- as described for Example 12-1. Starting from (2-fluoro-5- (hydroxymethyl) phenyl) cyclohexanol (9-7), the synthesis provides 2- (3-((1s, 4s) -4-((5-cyclopropyl-3 -(2,6-Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorophenyl) acetonitrile 12-2 was obtained.

ＭｅＯＨ中の臭化物（１．０当量）、ｄｐｐｐ（０．２当量）、Ｐｄ（ＯＡｃ）_２（０．２当量）、ＮＥｔ_３（２０当量）の溶液を、ＣＯ雰囲気下、６０℃で終夜撹拌し、冷却し、水で希釈し、ＥｔＯＡｃで２回抽出した。合わせた有機相をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、エバポレートし、残留物を分取ＴＬＣまたはフラッシュクロマトグラフィーによって精製して、実施例１３を生じさせた。 General Procedure 1E for Synthesis of Example 13

A solution of bromide (1.0 eq), dppp (0.2 eq), Pd (OAc) ₂ (0.2 eq), NEt ₃ (20 eq) in MeOH was stirred at 60 ° C. overnight in a CO atmosphere. Cool, dilute with water, and extract twice with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , evaporated, and the residue was purified by preparative TLC or flash chromatography to give Example 13.

(Example 13-1)
Methyl 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -7-fluorobenzo [d ] Thiazole-6-carboxylate

  According to general procedure 1E, (1s, 4s) -1- (6-bromo-7-fluorobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) Starting from isoxazol-4-yl) methoxy) cyclohexanol (6-5) and synthesized by methyl 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6) -Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -7-fluorobenzo [d] thiazole-6-carboxylate 13-1 was obtained.

(Example 13-2)
Methyl 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5,7-difluorobenzo [D] Thiazole-6-carboxylate

  According to general procedure 1E, (1s, 4s) -1- (6-bromo-5,7-difluorobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6 Starting from -dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanol (6-4) and synthesized by methyl 2-((1s, 4s) -4-((5-cyclopropyl-3- (2 , 6-Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5,7-difluorobenzo [d] thiazole-6-carboxylate 13-2.

ＭｅＯＨ中のエステル（１．０当量）の溶液に、ＬｉＯＨ・Ｈ_２Ｏ（１０当量）を添加し、混合物を室温で終夜撹拌し、濃縮し、水で希釈し、ｐＨ約４に酸性化し、ＥｔＯＡｃで２回抽出した。合わせた有機相をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、エバポレートし、残留物を、分取ＨＰＬＣによって精製して、実施例１４−１を生じさせた。 General Procedure 1F for the synthesis of Example 14

To a solution of the ester (1.0 eq) in MeOH was added LiOH.H ₂ O (10 eq) and the mixture was stirred at room temperature overnight, concentrated, diluted with water, acidified to pH ˜4, Extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , evaporated and the residue was purified by preparative HPLC to give Example 14-1.

(Example 14-1)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -7-fluorobenzo [d] Thiazole-6-carboxylic acid

According to general procedure 1F, methyl 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl)- Starting from 7-fluorobenzo [d] thiazole-6-carboxylate 13-1, it is synthesized by 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl). ) Isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -7-fluorobenzo [d] thiazole-6-carboxylic acid 14-1. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.40 (br s, 1H), 7.97-7.94 (m, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.66-7.56 (m, 3H), 6.40 (br s, 1H), 4.32 (s, 2H), 3.27-3.23 (m, 1H), 2.38-2.34 (m, 1H), 1.89-1.80 (m, 4H), 1.71-1.68 (m , 2H), 1.49-1.41 (m, 2H), 1.17-1.11 (m, 4H). LC / MS (ESI): m / z 577.0 (M + H) ⁺ .

(Example 14-2)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5,7-difluorobenzo [ d] thiazole-6-carboxylic acid

According to general procedure 1F, methyl 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl)- Starting from 5,7-difluorobenzo [d] thiazole-6-carboxylate 13-2, the synthesis yields 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6 -Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -5,7-difluorobenzo [d] thiazole-6-carboxylic acid 14-2 was obtained. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 14.05 (br s, 1H), 7.84 (d, J = 10.0 Hz, 1H), 7.66-7.60 (m, 2H), 7.58-7.56 (m, 1H), 6.43 (br s, 1H), 4.31 (s, 2H), 3.25-3.23 (m, 1H), 2.37-2.34 (m, 1H), 1.85-1.79 (m, 4H), 1.70-1.67 (m , 2H), 1.46-1.41 (m, 2H), 1.18-1.09 (m, 4H). LC / MS (ESI): m / z 595.0 (M + H) ⁺ .

(Example 14-3)
1- (3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3 2.1] octane-8-yl) -5-fluorophenoxy) cyclopropanecarboxylic acid

According to general procedure 1F, methyl 1- (3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) Starting from -8-hydroxybicyclo [3.2.1] octane-8-yl) -5-fluorophenoxy) cyclopropanecarboxylate (9-28), the synthesis gives 1- (3-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8- Yl) -5-fluorophenoxy) cyclopropanecarboxylic acid 14-3 was obtained. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.02 (br s, 1H), 7.66-7.56 (m, 3H), 6.84 (d, J = 10.5 Hz, 1H), 6.79 (s, 1H) , 6.60-6.57 (m, 1H), 4.26 (s, 2H), 3.46-3.41 (m, 1H), 2.37-2.34 (m, 1H), 2.26 (s, 2H), 1.80 (t, J = 11.0 Hz , 2H), 1.57-1.51 (m, 4H), 1.28-1.09 (m, 10H), hydroxyl protons are not resolved. LCMS (ESI): m / z 602.2 (M + H) ^<+> .

ｎ−ＢｕＬｉの溶液（ヘキサン中１．６Ｍ）（２当量）を、ＴＨＦ（１０容量）中のブロモ／ヨード誘導体（２当量）の溶液に、Ａｒ雰囲気下、−７８℃で２０分間にわたって滴下添加した。得られた溶液を−７８℃で２０分間にわたって撹拌し、次いで、ＴＨＦ（１０容量）中のケトンＩｎｔ−４（１当量）の溶液を２０分間にわたって滴下添加した。溶液を−７８℃でさらに２時間にわたって撹拌し、次いで、ＮＨ_４Ｃｌ（飽和）でクエンチした。反応混合物をＥｔＯＡｃで抽出し、有機層を合わせ、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮した。粗生成物をシリカゲルクロマトグラフィーによって精製した。 General Procedure 1G for Synthesis of Example 15

Add a solution of n-BuLi (1.6 M in hexane) (2 eq) dropwise to a solution of bromo / iodo derivative (2 eq) in THF (10 vol) over 20 min at −78 ° C. under Ar atmosphere. did. The resulting solution was stirred at −78 ° C. for 20 minutes, then a solution of ketone Int-4 (1 equivalent) in THF (10 vol) was added dropwise over 20 minutes. The solution was stirred at −78 ° C. for a further 2 hours and then quenched with NH ₄ Cl (saturated). The reaction mixture was extracted with EtOAc and the organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel chromatography.

(Example 15-1)
(1R, 3s, 5S, 8r) -8- (6-Bromobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl ) Methoxy) bicyclo [3.2.1] octane-8-ol

According to general procedure 1G, (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane Synthetic (1R, 3s, 5S, 8r) -8- (6-bromobenzo [d] thiazole starting from -8-one (Int-4-14a) and 2,6-dibromobenzo [d] thiazole 2-yl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol 15-1 Obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 8.02 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.58 (dd, J = 8.8 Hz, J = 2.0 Hz , 1H), 7.44-7.33 (m, 3H), 4.35 (s, 2H), 3.65-3.59 (m, 1H), 2.22-2.16 (m, 1H), 2.04-1.73 (m, 8H), 1.53-1.48 (m, 2H), 1.30-1.24 (m, 2H), 1.16-1.10 (m, 2H), hydroxyl protons are not resolved. MS (ESI): m / z 620.5 (M + l) ^<+> .

(Example 15-2)
(1R, 3r, 5S, 8r) -8- (6-Bromobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl ) Methoxy) bicyclo [3.2.1] octane-8-ol

  According to general procedure 1G, (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane Synthetic (1R, 3r, 5S, 8r) -8- (6-bromobenzo [d] thiazole starting from -8-one (Int-4-14b) and 2,6-dibromobenzo [d] thiazole 2-yl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol 15-2 Obtained.

(Example 15-3)
(1R, 3s, 5S, 8r) -8- (4-Bromo-2-fluorophenyl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) Bicyclo [3.2.1] octane-8-ol

  According to general procedure 1G, (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane Starting from -8-one (Int-4-14a) and 4-bromo-2-fluoro-1-iodobenzene, the synthesis provides (1R, 3s, 5S, 8r) -8- (4-bromo-2 -Fluorophenyl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol 15-3 It was.

(Example 15-4)
(1R, 3s, 5S, 8r) -8- (3-Bromophenyl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3. 2.1] Octane-8-ol

  According to general procedure 1G, (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane Starting from -8-one (Int-4-14a) and 1,3-dibromobenzene, the synthesis provides (1R, 3s, 5S, 8r) -8- (3-bromophenyl) -3-((5 -Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol 15-4 was obtained.

(Example 15-5)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) isonicotinonitrile

  According to general procedure 1G, (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane Starting from -8-one (Int-4-14a) and 2-bromoisonicotinonitrile, the synthesis gave 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3 -(2,6-Dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) isonicotinonitrile 15-5 was obtained.

(Example 15-6)
(1R, 3s, 5S, 8r) -8- (6-Bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) iso Oxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol

  According to general procedure 1G, (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane Starting from -8-one (Int-4-14a) and 6-bromo-4-fluorobenzo [d] thiazol-2-amine (Int-6-5), the synthesis gives (1R, 3s, 5S, 8r) -8- (6-Bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy ) Bicyclo [3.2.1] octane-8-ol 15-6 was obtained.

(Example 15-7)
(1R, 3s, 5S, 8r) -8- (6-Bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) ) Isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane-8-ol

  According to general procedure 1G, (1R, 3s, 5S) -3-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1 ] Starting from octan-8-one (Int-4-15) and 6-bromo-4-fluorobenzo [d] thiazol-2-amine (Int-6-5), the synthesis provides (1R, 3s, 5S, 8r) -8- (6-Bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2- (difluoromethoxy) phenyl) isoxazole-4 -Yl) methoxy) bicyclo [3.2.1] octane-8-ol 15-7 was obtained.

(Example 15-8)
(1R, 3s, 5S, 8r) -8- (6-Bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (3,5-dichloropyridine- 4-yl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol

According to general procedure 1G, (1R, 3s, 5S) -3-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) bicyclo [3. 2.1] Synthetic (1R) starting from octan-8-one (Int-4-16) and 6-bromo-4-fluorobenzo [d] thiazol-2-amine (Int-6-5) , 3s, 5S, 8r) -8- (6-Bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (3,5-dichloropyridine-4-) Yl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane-8-ol 15-8.
(Example 15-9)
(1s, 4s) -1- (6-Bromobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexane -1-ol

  Following general procedure 1G, 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone (Int-4-4) and 2,6-dibromobenzo [d ] Starting from thiazole, the synthesis provides (1s, 4s) -1- (6-bromobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) Isoxazol-4-yl) methoxy) cyclohexane-1-ol 15-9 was obtained.

(Example 15-10)
(1s, 4s) -1- (6-Bromo-4-fluorobenzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4- Yl) methoxy) cyclohexane-1-ol

  According to general procedure 1G, 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone (Int-4-4) and 6-bromo-4-fluorobenzo Starting from [d] thiazol-2-amine (Int-6-5), (1s, 4s) -1- (6-bromo-4-fluorobenzo [d] thiazol-2-yl)-is synthesized by synthesis. 4-((5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexane-1-ol 15-10 was obtained.

(Example 15-11)
2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1 ] Octane-8-yl) benzo [d] thiazole-6-carbonitrile

  According to general procedure 1G, (1R, 3s, 5S) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) bicyclo [3.2.1] octane- Starting from 8-one (Int-4-17) and 2-bromobenzo [d] thiazole-6-carbonitrile, the synthesis provides 2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole-6-carbonitrile 15- 11 was obtained.

(Example 15-12)
2-((1R, 3r, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1 ] Octane-8-yl) benzo [d] thiazole-6-carbonitrile

  According to general procedure 1G, (1R, 3r, 5S) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) bicyclo [3.2.1] octane- Starting from 8-one (Int-4-18) and 2-bromobenzo [d] thiazole-6-carbonitrile, the synthesis gives 2-((1R, 3r, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-methylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole-6-carbonitrile 15- 12 was obtained.

(Examples 15-13)
2-((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy-3-methylbicyclo [3. 2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

  According to general procedure 1G, (1R, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-methylbicyclo [3.2.1 ] Starting from octan-8-one (Int-4-19) and 6-bromo-4-fluorobenzo [d] thiazol-2-amine (Int-6-5), the synthesis yields 2-((1R , 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy-3-methylbicyclo [3.2.1] octane -8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile 15-13 was obtained as a single isomer.

(Examples 15-14)
2-((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3- (difluoromethyl) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

  According to general procedure 1G, (1R, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3- (difluoromethyl) bicyclo [3. 2.1] Starting from octan-8-one (Int-4-20) and 6-bromo-4-fluorobenzo [d] thiazol-2-amine (Int-6-5), the synthesis yields 2- ((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3- (difluoromethyl) -8-hydroxybicyclo [3 2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile 15-14 was obtained as a single isomer.

(Examples 15-15)
2-((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy-3- (methoxymethyl) bicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

  According to general procedure 1G, 5-cyclopropyl-3- (2,6-dichlorophenyl) -4-((((1R, 5S) -3- (methoxymethyl) spiro [bicyclo [3.2.1] octane- 8,2 '-[1,3] dioxolane] -3-yl) oxy) methyl) isoxazole (Int-4-21) and 6-bromo-4-fluorobenzo [d] thiazol-2-amine (Int- 6-5) by synthesis, 2-((1R, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-Hydroxy-3- (methoxymethyl) bicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile 15-15 as a single isomer It was.

(Examples 15-16)
(1s, 4s) -1- (7- (1,3-Dioxolan-2-yl) benzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) ) Isoxazol-4-yl) methoxy) cyclohexane-1-ol

  According to general procedure 1G, 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone (Int-4-4) and 7- (1,3-dioxolane 2-yl) benzo [d] thiazole Int-6-8 was synthesized by synthesis from (1s, 4s) -1- (7- (1,3-dioxolan-2-yl) benzo [d] thiazole. -2-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexane-1-ol 15-16 was obtained.

(Examples 15-17)
(1s, 4s) -1- (4-Chloroquinolin-7-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexane-1- Oar

  According to general procedure 1G, 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone (Int-4-4) and 7-bromo-4-chloroquinoline Starting from the synthesis, (1s, 4s) -1- (4-chloroquinolin-7-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4- Yl) methoxy) cyclohexane-1-ol 15-17 was obtained.

(Examples 15-18)
6- (4-((5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-4-carbonitrile

  According to general procedure 1G 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone (Int-4-4) and 6-iodoquinoline-4-carbo Starting from the nitrile Int-6-9, the synthesis gives 6- (4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) Quinoline-4-carbonitrile 15-18 was obtained.

(Examples 15-19)
(1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- (3- (hydroxymethyl) benzo [d] isothiazole- 5-yl) cyclohexane-1-ol

According to general procedure 1G, 4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexanone (Int-4-4) and (5-bromobenzo [d] iso (1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) by synthesis starting from thiazol-3-yl) methanol Int-6-10 ) Methoxy) -1- (3- (hydroxymethyl) benzo [d] isothiazol-5-yl) cyclohexane-1-ol 15-19.
(Examples 15-20)
2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-isopropylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1 ] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

  According to general procedure 1G, intermediate (1R, 3s, 5S) -3-((3- (2,6-dichlorophenyl) -5-isopropylisoxazol-4-yl) methoxy) bicyclo [3.2.1] Starting from octan-8-one Int-4-25 and 2-bromo-4-fluorobenzo [d] thiazole-6-carbonitrile Int-6-1, the title compound 2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5-isopropylisoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4- Fluorobenzo [d] thiazole-6-carbonitrile (15-20) was synthesized (the minor isomer was not isolated).

(Example 15-21)
2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) isoxazol-4-yl) methoxy) -8 -Hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

  Following the general procedure 1G, intermediate (1R, 3s, 5S) -3-((3- (2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) isoxazol-4-yl) methoxy ) Starting from bicyclo [3.2.1] octane-8-one Int-4-26 and 2-bromo-4-fluorobenzo [d] thiazole-6-carbonitrile Int-6-1, the title compound 2 -((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5- (2-fluoropropan-2-yl) isoxazol-4-yl) methoxy) -8- Hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (15-21) was synthesized (the minor isomer was not isolated).

(Examples 15-22)
2-((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5- (2-hydroxypropan-2-yl) isoxazol-4-yl) methoxy) -8 -Hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

  According to general procedure 1G, intermediate (1R, 3s, 5S) -3-((3- (2,6-dichlorophenyl) -5- (2-hydroxypropan-2-yl) isoxazol-4-yl) methoxy ) Starting from bicyclo [3.2.1] octane-8-one Int-4-27 and 2-bromo-4-fluorobenzo [d] thiazole-6-carbonitrile Int-6-1, the title compound 2 -((1R, 3s, 5S, 8r) -3-((3- (2,6-dichlorophenyl) -5- (2-hydroxypropan-2-yl) isoxazol-4-yl) methoxy) -8- Hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (15-22) was synthesized (the minor isomer was not isolated).

(Examples 15-23)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [ 3.2.1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile

  Following the general procedure 1G, the intermediate (1R, 3s, 5S) -3-((5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) isoxazol-4-yl) methoxy) bicyclo [3 2.1] Octan-8-one Int-4-24 and 2-bromo-4-fluorobenzo [d] thiazole-6-carbonitrile Int-6-1 starting from title compound 2-((1R , 3s, 5S, 8r) -3-((5-cyclopropyl-3-((2,6-dimethylphenoxy) methyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1 ] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (15-23) was synthesized (the minor isomer was not isolated).

(Examples 15-24)
(1R, 3s, 5S, 8r) -8- (6-Bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((4-cyclopropyl-1- (2,6-dichlorophenyl)- 1H-pyrazol-5-yl) methoxy) bicyclo [3.2.1] octan-8-ol

  According to general procedure 1G, (1R, 3s, 5S) -3-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) bicyclo [3.2.1 ] Starting from octan-8-one (Int-4-28) and 6-bromo-4-fluorobenzo [d] thiazol-2-amine Int-6-5, the synthesis provides (1R, 3s, 5S, 8r) -8- (6-Bromo-4-fluorobenzo [d] thiazol-2-yl) -3-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) ) Methoxy) bicyclo [3.2.1] octane-8-ol 15-24 was obtained.

(Example 16)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluoro-N- ( Methylsulfonyl) benzo [d] thiazole-6-carboxamide

2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4 in DMF (10 mL) -Fluorobenzo [d] thiazole-6-carboxylic acid 11-31 (200 mg, 0.35 mmol) in a solution of EDCI (134 mg, 0.7 mmol), DMAP (85 mg, 0.7 mmol) and methanesulfonamide (67 mg, 0.7 mmol) was added. The mixture was stirred at room temperature for 12 hours, diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried, concentrated and purified by preparative HPLC to give 2-((1s, 4s) -4-((5-cyclopropyl-3- (2, 6-Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluoro-N- (methylsulfonyl) benzo [d] thiazole-6-carboxamide 16 was obtained. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 12.30 (br s, 1H), 8.57 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.0 Hz, J = 1.5 Hz, 1H ), 7.67-7.56 (m, 3H), 6.34 (br s, 1H), 4.33 (s, 2H), 3.41 (s, 3H), 3.30-3.25 (m, 1H), 2.40-2.33 (m, 1H) , 1.92-1.65 (m, 6H), 1.49-1.38 (m, 2H), 1.20-1.10 (m, 4H). LCMS (ESI): m / z 654.0 (M + H) ⁺ .

(Example 17)
2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4- Fluoro-N- (2-morpholinoethyl) benzo [d] thiazole-6-carboxamide

2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4- In the same manner as described in Example 16, except that fluorobenzo [d] thiazole-6-carboxylic acid 11-24 and 2-morpholinoethanamine are used as starting materials, the title compound 2-(( 1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluoro-N- (2-morpholinoethyl) benzo [d] thiazole-6-carboxamide 17 was prepared. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 8.85 (s, 2H), 8.58 (t, J = 5.5 Hz, 1H), 8.40 (s, 1H), 7.76 (d, J = 12.0 Hz, 1H), 6.28 (s, 1H), 4.39 (s, 2H), 3.58 (t, J = 4.8 Hz, 4H), 3.42 (q, J = 6.5 Hz, 2H), 3.31-3.28 (m, 1H), 2.51-2.38 (m, 7H), 1.93-1.79 (m, 4H), 1.69-1.65 (m, 2H), 1.45-1.37 (m, 2H), 1.21-1.11 (m, 4H). LCMS (ESI): m / z 690.2 (M + H) ⁺ .

(Example 18)
2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4- Fluorobenzo [d] thiazole-6-carboxamide

2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1- in EtOH (5 mL) To a solution of hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carbonitrile (9-20) (200 mg, 0.36 mmol) was added aqueous NaOH (1N, 1 mL) and the mixture was added at 75 ° C. for 1 Stir over time, cool, acidify with HCl (4M, 1 mL) and extract with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL), dried, concentrated and purified by preparative HPLC to give 2-((1s, 4s) -4-((5-cyclopropyl-3- (3 5-Dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carboxamide 18 was obtained. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 8.85 (s, 2H), 8.44 (s, 1H), 8.12 (s, 1H), 7.80 (d, J = 11.5 Hz, 1H), 7.59 ( s, 1H), 6.28 (br s, 1H), 4.39 (s, 2H), 3.32-3.25 (m, 1H), 2.40-2.35 (m, 1H), 1.92-1.65 (m, 6H), 1.46-1.37 (m, 2H), 1.19-1.10 (m, 4H). LCMS (ESI): m / z 577.0 (M + H) ^<+> .

(Example 19)
Methyl 2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4 -Fluorobenzo [d] thiazole-6-carboxylate

2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazole-4-] in a mixture of THF (8 mL) and MeOH (2 mL). Yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carboxylic acid (11-24) (200 mg, 0.35 mmol) in a solution of TMSCHN ₂ (2M in hexane, 0.4 mL). , 0.8 mmol) was added at 0 ° C. The mixture was stirred at room temperature for 2 hours, diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried, concentrated and purified by silica gel column (DCM / EtOAc = 10: 1) to give methyl 2-((1s, 4s) -4-((5 -Cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carboxylate 19 It was.

(Example 20)
(1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy) -1- (4-fluoro-6- (2 -Hydroxypropan-2-yl) benzo [d] thiazol-2-yl) cyclohexanol

Methyl 2-((1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy)-in dry THF (10 mL) To a solution of 1-hydroxycyclohexyl) -4-fluorobenzo [d] thiazole-6-carboxylate (19) (200 mg, 0.34 mmol) was added MeMgBr (3 M in Et ₂ O, 1.2 mL, 3.6 mmol). Slowly added at -10 ° C. The mixture was stirred at room temperature for 2 hours, diluted with aqueous NH ₄ Cl (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried, concentrated and purified by preparative HPLC to give (1s, 4s) -4-((5-cyclopropyl-3- (3,5-dichloro). Pyridin-4-yl) isoxazol-4-yl) methoxy) -1- (4-fluoro-6- (2-hydroxypropan-2-yl) benzo [d] thiazol-2-yl) cyclohexanol 20 is obtained. It was. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 8.85 (s, 2H), 7.92 (s, 1H), 7.40 (d, J = 12.5 Hz, 1H), 6.16 (s, 1H), 5.27 ( s, 1H), 4.38 (s, 2H), 3.31-3.24 (m, 1H), 2.41-2.35 (m, 1H), 1.91-1.77 (m, 4H), 1.68-1.64 (m, 2H), 1.47 ( s, 6H), 1.44-1.34 (m, 2H), 1.19-1.11 (m, 4H). LCMS (ESI): m / z 592.1 (M + H) ⁺ .

(Example 21)
(1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- (4-fluoro-6- (1H-tetrazole-5- Yl) benzo [d] thiazol-2-yl) cyclohexanol

2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) -4 in DMF (20 mL) - fluoro benzo [d] thiazole-6-carbonitrile 8-13 (300 mg, 0.54 mmol) to a solution _of, NaN 3 _(350mg, 5.4mmol) and _NH 4 Cl (290mg, 5.4mmol) was added, The mixture was stirred at 120 ° C. for 12 hours, cooled, diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried, concentrated and purified by preparative HPLC to give (1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl). ) Isoxazol-4-yl) methoxy) -1- (4-fluoro-6- (1H-tetrazol-5-yl) benzo [d] thiazol-2-yl) cyclohexanol 21 was obtained. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 8.64 (s, 1H), 7.95 (d, J = 11.0 Hz, 1H), 7.67-7.57 (m, 3H), 6.33 (br s, 1H) , 4.33 (s, 2H), 3.31-3.24 (m, 1H), 2.40-2.34 (m, 1H), 1.95-1.65 (m, 6H), 1.46-1.38 (m, 2H), 1.20-1.09 (m, 4H), tetrazole hydrogen is not resolved. LCMS (ESI): m / z 600.7 (M + H) ⁺

(Example 22)
4- (4-((((1R, 3s, 5S, 8r) -8- (6-carboxy-4-fluorobenzo [d] thiazol-2-yl) -8-hydroxybicyclo [3.2.1] Octane-3-yl) oxy) methyl) -5-cyclopropylisoxazol-3-yl) -3,5-dichloropyridine 1-oxide

2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (3,5-dichloropyridin-4-yl) isoxazol-4-yl) methoxy in AcOH (5 mL) ) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid (11-29) (150 mg, 0.25 mmol) in a solution of H ₂ O ₂ (30% aqueous solution; 3.0 mL) was added and the resulting mixture was heated at 50 ° C. for an additional 12 hours, quenched by the addition of saturated NaHSO ₃ solution and with EtOAc (3 × 10 mL). Extracted. The combined organic layers were washed with brine (10 mL), concentrated and purified twice by preparative HPLC to give 4- (4-((((1R, 3s, 5S, 8r) -8- (6-carboxyl. -4-fluorobenzo [d] thiazol-2-yl) -8-hydroxybicyclo [3.2.1] octane-3-yl) oxy) methyl) -5-cyclopropylisoxazol-3-yl) -3 , 5-dichloropyridine 1-oxide 22 was obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 13.23 (br s, 1H), 8.79 (s, 2H), 8.56 (s, 1H), 7.76 (d, J = 11.2 Hz, 1H ), 6.57 (s, 1H), 4.36 (s, 2H), 3.67-3.55 (m, 1H), 2.41-2.36 (m, 3H), 1.88-1.82 (m, 4H), 1.77-1.65 (m, 2H ), 1.55-1.46 (m, 2H), 1.19-1.05 (m, 4H). MS (ESI): m / z 619.8 (M + 1) ⁺ .

(Example 23a) and (Example 23b)
(1R, 2r, 3S, 5s, 7s) -2- (6-Bromobenzo [d] thiazol-2-yl) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4 -Yl) methoxy) adamantan-2-ol 23a and (1R, 2s, 3S, 5s, 7s) -2- (6-bromobenzo [d] thiazol-2-yl) -5-((5-cyclopropyl-3) -(2,6-dichlorophenyl) isoxazol-4-yl) methoxy) adamantan-2-ol 23b

(1R, 3S, 5s, 7s) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) adamantan-2-one Int- in THF (10 mL) A solution of 8-3 (600 mg, 1.39 mmol) and 2,6-dibromobenzo [d] thiazole (815 mg, 2.78 mmol) was cooled to −78 ° C. under Ar atmosphere and then n-BuLi (1. 6M, 1.56 mL, 2.5 mmol) was added dropwise at −78 ° C. over 20 minutes. The solution was stirred at −78 ° C. for an additional 2 hours, then quenched with NH ₄ Cl (saturated) and extracted with EtOAc (3 × 10 mL). The organic layers were combined, washed with brine (2 × 10 mL), dried over Na ₂ SO ₄ , concentrated and purified by chromatography to give the minor isomer (1R, 2r, 3S, 5s, 7s) -2- (6-Bromobenzo [d] thiazol-2-yl) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) adamantan-2-ol 23a and major isomerism Form (1R, 2s, 3S, 5s, 7s) -2- (6-Bromobenzo [d] thiazol-2-yl) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole- 4-yl) methoxy) adamantan-2-ol 23b (500 mg) was obtained.

(Example 24a) and (Example 24b)
(1R, 2r, 3S, 5s, 7s) -2- (Benzo [d] thiazol-2-yl) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) ) Methoxy) adamantan-2-ol 24a and (1R, 2s, 3S, 5s, 7s) -2- (benzo [d] thiazol-2-yl) -5-((5-cyclopropyl-3- (2, 6-dichlorophenyl) isoxazol-4-yl) methoxy) adamantan-2-ol 24b

(1R, 3S, 5s, 7s) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) adamantan-2-one Int-8-3 (50 mg, 116 μmol) and 2-bromobenzo [d] thiazole (50 mg, 232 μmol) were treated as described in Example 23 to give the minor isomer (1R, 2r, 3S, 5s, 7s) -2- ( Benzo [d] thiazol-2-yl) -5-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) adamantan-2-ol 24a and the major isomer (1R , 2s, 3S, 5s, 7s) -2- (benzo [d] thiazol-2-yl) -5-((5-cyclopropyl-3- (2,6-dichloro) Rophenyl) isoxazol-4-yl) methoxy) adamantan-2-ol 24b was obtained. 24a: ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.06 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.65-7.62 (m, 2H), 7.60-7.53 (m, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.2 Hz, 1H), 5.97 (s, 1H), 4.24 (s, 2H), 2.43-2.38 (m, 2H), 2.35-2.30 (m, 1H), 2.19-2.13 (m, 2H), 1.93-1.84 (m, 3H), 1.49-1.37 (m, 4H), 1.29-1.21 (m, 2H) 1.18-1.06 (m, 4H). MS (ESI): m / z 566.9 (M + 1) ⁺ . 24b: ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.15 (d, J = 7.2 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.58-7.47 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.91 (t, J = 8.0 Hz, 1H), 5.92 (s, 1H), 4.15 (s, 2H), 2.52-2.47 (m, 2H), 2.40-2.15 (m, 3H), 2.02-1.98 (m, 1H), 1.53-1.23 (m, 9H), 1.08-0.98 (m, 4H). MS (ESI): m / z 566.9 (M + 1) ⁺ .

(Example 25)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-7- Carval Dehydr

(1s, 4s) -1- (7- (1,3-Dioxolan-2-yl) benzo [d] thiazol-2-yl) -4-((5-cyclopropyl-3-) in acetone (20 mL) To a solution of (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) cyclohexane-1-ol 15-16 (1.2 g, 2.0 mmol) was added H ₂ SO ₄ (2.0 mL) at room temperature. The mixture was stirred at room temperature overnight, diluted with EtOAc (100 mL) and washed with saturated NaHCO ₃ . The organic phase was dried over Na ₂ SO ₄ , concentrated and purified by chromatography to give 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole). -4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-7-carbaldehyde 25 was obtained.

(Example 26)
2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-7- carboxylic acid

To a solution of KMnO ₄ (1.0 g) in H ₂ O (50 mL) was added H ₂ SO ₄ (1.0 mL). This solution was then added to 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1 in acetone (10 mL). -Hydroxycyclohexyl) benzo [d] thiazole-7-carbaldehyde 25 (400 mg, 0.74 mmol) was slowly added and stirring was continued until the starting material was consumed. The mixture was filtered, diluted with EtOAc and washed with brine. The organic phase was dried, concentrated and purified by preparative HPLC to give the title compound 2-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4 -Yl) methoxy) -1-hydroxycyclohexyl) benzo [d] thiazole-7-carboxylic acid 26 was obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.62 (br s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.67-7.56 ( m, 4H), 6.06 (s, 1H), 4.32 (s, 2H), 3.26-3.21 (m, 1H), 2.40-2.32 (m, 1H), 1.91-1.74 (m, 4H), 1.73-1.67 ( m, 2H), 1.50-1.43 (m, 2H), 1.19-1.10 (m, 4H). LC / MS (ESI): m / z 559.5 (M + H) ⁺ .

(Example 27)
(1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- (4-iodoquinolin-7-yl) cyclohexane-1- Oar

(1s, 4s) -1- (4-Chloroquinolin-7-yl) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) in acetone (20 mL) A mixture of methoxy) cyclohexane-1-ol 15-17 (1.05 g, 1.96 mmol) and KI (1.66 g, 10.0 mmol) was heated to reflux overnight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated and the residue was diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , concentrated and the product (1s, 4s) -4-((5-cyclopropyl-3- ( 2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- (4-iodoquinolin-7-yl) cyclohexane-1-ol 27 was obtained and used in the next step without purification. did.

(Example 28)
7-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-4-carbonitrile

(1s, 4s) -4-((5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- (4-iodoquinoline-7- in DMF (10 mL) Yl) A mixture of cyclohexane-1-ol 27 (1.3 g, 1.96 mmol), Zn (CN) ₂ (468 mg, 4.0 mmol) and Pd (PPh ₃ ) ₄ (230 mg, 0.2 mmol) with N ₂ . I was degassed. The mixture was stirred at 125 ° C. overnight, cooled to room temperature, diluted with EtOAc, washed with brine and dried over Na ₂ SO ₄ . The solution was concentrated and purified by chromatography to give 7-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1 -Hydroxycyclohexyl) quinoline-4-carbonitrile 28 was produced.

(Example 29)
7-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-4-carboxylic acid

7-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline- in EtOH (10 mL) To a solution of 4-carbonitrile 28 (460 mg, 0.86 mmol) was added aqueous NaOH (20%, 10 mL) and the reaction was refluxed overnight, cooled to room temperature, concentrated, diluted with water and aqueous HCl. Acidified with The mixture was then extracted with EtOAc and the organic phase was dried over Na ₂ SO ₄ , concentrated and purified by preparative HPLC to give 7-((1s, 4s) -4-((5-cyclopropyl-3 -(2,6-Dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-4-carboxylic acid 29 was obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.83 (br s, 1H), 9.00 (d, J = 4.4 Hz, 1H), 8.61 (d, J = 8.8 Hz, 1H), 8.13 (s, 1H), 7.86 (d, J = 4.0 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.68-7.65 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 5.07 ( s, 1H), 4.33 (s, 2H), 3.29-3.25 (m, 1H), 2.38-2.33 (m, 1H), 1.83-1.49 (m, 8H), 1.18-1.12 (m, 4H) .LC / MS (ESI): m / z 553.5 (M + H) ^<+> .

(Example 30) and (Example 31)
6-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-4-carboxylic acid (30 ) And 6-((1r, 4r) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-4-carboxylic acid (31)

6- (4-((5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-4-carbonitrile in EtOH (10 mL) 15- To a solution of 18 (460 mg, 0.86 mmol) was added aqueous NaOH (20%, 10 mL) and the reaction was refluxed overnight, cooled to room temperature, concentrated, diluted with water and acidified with aqueous HCl. . The mixture was then extracted with EtOAc and the organic phase was dried over Na ₂ SO ₄ , concentrated, purified by preparative HPLC and separated 6-((1s, 4s) -4-((5-cyclopropyl -3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-4-carboxylic acid 30 (major isomer) and 6-((1r, 4r) -4- ( This gave (5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) quinoline-4-carboxylic acid 31 (minor isomer). 30: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 14.0 (br s, 1H), 9.04 (d, J = 4.0 Hz, 1H), 8.82 (s, 1H), 8.10 (d, J = 8.8 Hz , 1H), 7.99-7.93 (m, 2H), 7.75-7.67 (m, 3H), 4.39 (s, 2H), 3.35-3.30 (m, 1H), 2.47-2.40 (m, 1H), 1.84-1.57 (m, 8H), 1.24-1.18 (m, 5H). LC / MS (ESI): m / z 553.1 (M + H) ^<+> . 31: LC / MS (ESI): m / z 553.1 (M + H) ⁺ .

(Example 32)
5-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] isothiazole-3 -Carval Dehydr

(1s, 4s) -4-((5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1- (3- (hydroxymethyl) benzone in DCM (10 mL) To a solution of [d] isothiazol-5-yl) cyclohexane-1-ol 15-19 (500 mg, 0.91 mmol), the desmartin reagent was added in small portions at 0 ° C. until the starting material was consumed. PE (20 mL) was added to the reaction and the mixture was filtered. The filtrate was washed with saturated NaHCO ₃ and brine. The organic phase was dried, concentrated and purified by chromatography to give 5-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl). Methoxy) -1-hydroxycyclohexyl) benzo [d] isothiazole-3-carbaldehyde 32 was generated. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.28 (s, 1H), 8.84 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.50-7.35 (m, 3H), 4.39 (s, 2H), 3.33-3.27 (m, 1H), 2.25-2.15 (m, 1H), 1.89-1.65 (m, 8H), 1.32-1.22 (m, 2H ), 1.17-1.14 (m, 2H), hydroxyl protons are not resolved.

(Example 33)
5-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] isothiazole-3 -Carboxylic acid

H ₂ O (3 mL) and 5 in EtOAc (5mL) - ((1s , 4s) -4 - ((5- cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) - To a mixture of 1-hydroxycyclohexyl) benzo [d] isothiazole-3-carbaldehyde 32 (240 mg, 0.44 mmol) was added oxone (168 mg, 1.0 mmol). The reaction was stirred at room temperature for 5 hours, diluted with EtOAc and washed with brine. The organic phase was dried (Na ₂ SO ₄ ), concentrated and purified by preparative HPLC to give 5-((1s, 4s) -4-((5-cyclopropyl-3- (2,6-dichlorophenyl)). Isoxazol-4-yl) methoxy) -1-hydroxycyclohexyl) benzo [d] isothiazole-3-carboxylic acid 33 was produced. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.62 (br s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.67-7.56 ( m, 4H), 6.06 (s, 1H), 4.32 (s, 2H), 3.26-3.21 (m, 1H), 2.40-2.32 (m, 1H), 1.91-1.67 (m, 6H), 1.50-1.43 ( m, 2H), 1.12-1.09 (m, 4H). LC / MS (ESI): m / z 559.5 (M + H) ⁺ .

(Example 34)
(1R, 3s, 5S, 8r) -8- (1H- [1,2,3] triazolo [4,5-b] pyridin-6-yl) -3-((5-cyclopropyl-3- (2 , 6-Dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol

To a solution of SEM protected intermediate Int-10a (major isomer, 150 mg, 0.23 mmol) in EtOAc (2 mL) was added HCl / EtOAc (2.0 M, 0.5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours, concentrated and purified by preparative HPLC to give (1R, 3s, 5S, 8r) -8- (1H- [1,2,3] triazolo [4,5-b ] Pyridin-6-yl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol 34. Was generated. The same procedure was applied to the SEM protected intermediate Int-10b (minor isomer). The same final compound 34 was obtained. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 16.26 and 15.89 (2 br s, 1H), 8.85 (s, 1H), 8.42 and 8.21 (2 br s, 1H), 7.67-7.65 (m, 2H), 7.60-7.56 (m, 1H), 5.35 (s, 1H), 4.30 (s, 2H), 3.52-3.47 (m, 1H), 2.56-2.53 (m, 2H), 2.41-2.34 (m, 1H), 1.92 (t, J = 11.2 Hz, 2H), 1.64-1.62 (m, 2H), 1.36-1.31 (m, 4H), 1.19-1.08 (m, 4H). LC / MS (ESI): m / Z 526.0 (M ⁺ H) ⁺ .

(Example 35)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) -4-fluoro-N-hydroxybenzo [d] thiazole-6-carboximidamide

2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) in EtOH (4 mL) and H ₂ O (1 mL) )) Methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile 8-9 (150 mg, 0.26 mmol) ₂ CO ₃ (55 mg, 0.52 mmol) and hydroxylamine hydrochloride (36 mg, 0.52 mmol) were added. The mixture was stirred at 70 ° C. overnight, diluted with water and extracted with EtOAc. The organic portion was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2 , 6-Dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluoro-N-hydroxybenzo [d] thiazole-6-carboximide Amide 35 was obtained.

(Example 36)
3- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3 2.1] octane-8-yl) -4-fluorobenzo [d] thiazol-6-yl) -1,2,4-oxadiazol-5 (2H) -one

2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy in THF (5 mL) To a solution of bicyclo [3.2.1] octane-8-yl) -4-fluoro-N-hydroxybenzo [d] thiazole-6-carboximidamide 35 (118 mg, 0.19 mmol) was added CDI (92 mg, 0 .57 mmol) and DBU (87 mg, 0.57 mmol) were added. The mixture was stirred at room temperature for 30 minutes, acidified with HCl (1M) and then extracted with EtOAc. The organic portion was washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give 3- (2-((1R, 3s, 5S, 8r) -3- ( (5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] Thiazol-6-yl) -1,2,4-oxadiazol-5 (2H) -one 36 was obtained. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 13.10 (br s, 1H), 8.42 (d, J = 1.0 Hz, 1H), 7.74-7.57 (m, 4H), 6.57 (s, 1H) , 4.29 (s, 2H), 3.54-3.48 (m, 1H), 2.40-2.35 (m, 3H), 1.85-1.79 (m, 4H), 1.65-1.60 (m, 2H), 1.45-1.41 (m, 2H), 1.19-1.09 (m, 4H). LC / MS (ESI): m / z 643.2 (M + H) ⁺ .

(Example 37)
Ethyl 2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [ 3.2.1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxamide) acetate

2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy in DMF (10 mL) To a solution of bicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-27 (150 mg, 0.25 mmol) was added EDCI (100 mg, 0.5 mmol). , DMAP (60 mg, 0.5 mmol) and glycine ethyl ester hydrochloride (70 mg, 0.5 mmol) were added and the mixture was stirred at room temperature for 12 hours, diluted with water (100 mL) and EtOAc (3 × 100 mL) Extracted with. The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified by column chromatography (DCM / MeOH = 100: 1) to give ethyl 2- (2- ((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxamide) acetate 37 was obtained.

(Example 38)
2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3 2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxamido) acetic acid

Ethyl 2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) in MeOH (50 mL) To a solution of -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxamide) acetate 37 (100 mg, 0.15 mmol), an aqueous NaOH solution (1N, 10 mL) was added and the mixture was stirred at room temperature for 5 h, acidified with HCl (4 M, 10 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, concentrated and purified by preparative HPLC to give 2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluoro Benzo [d] thiazole-6-carboxamide) acetic acid 38 was obtained. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 12.66 (br s, 1H), 9.03 (t, J = 6.0 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 7.81-7.58 (m, 4H), 6.53 (br s, 1H), 4.29 (s, 2H), 3.97 (d, J = 5.5 Hz, 2H), 3.55-3.50 (m, 1H), 2.40-2.36 (m, 3H) , 1.85-1.79 (m, 4H), 1.65-1.61 (m, 2H), 1.45-1.41 (m, 2H), 1.19-1.12 (m, 4H). LCMS (ESI): m / z 660.1 (M + H) ⁺ .

(Example 39)
2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3 2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxamido) ethanesulfonic acid, ammonia salt

2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy in DMF (10 mL) To a solution of bicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 11-27 (150 mg, 250 μmol), EDCI (100 mg, 500 μmol), DMAP (60 mg , 500 μmol) and taurine (63 mg, 500 μmol) were added and the mixture was stirred at room temperature for 12 hours, diluted with water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL) and concentrated. The residue was redissolved in MeOH (5 mL), 1N NH ₄ OH (0.5 mL) was added, concentrated and then purified by preparative HPLC to give 2- (2-((1R, 3s, 5S , 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl)- 4-Fluorobenzo [d] thiazole-6-carboxamido) ethanesulfonic acid 39 ammonia salt was obtained. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 8.66 (t, J = 5.5 Hz, 1H), 8.35 (d, J = 1.0 Hz, 1H), 7.71-7.58 (m, 4H), 7.20- 6.98 (m, 3H), 6.51 (s, 1H), 4.29 (s, 2H), 3.57-3.49 (m, 3H), 2.69 (t, J = 7.3 Hz, 2H), 2.41-2.36 (m, 3H) , 1.85-1.76 (m, 4H), 1.64-1.60 (m, 2H), 1.43-1.40 (m, 2H), 1.20-1.10 (m, 4H). LCMS (ESI): m / z 710.0 (M− NH ₃ ) ⁺ .

(Example 40) and (Example 41)
2-((1R, 5S) -8-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-hydroxybicyclo [3.2.1] octane- 3-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (40, first eluting isomer) and 2-((1R, 5S) -8-((5-cyclopropyl-3- ( 2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-hydroxybicyclo [3.2.1] octane-3-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (41, The second eluting isomer)

Compound (1R, 5S) -8-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octane in dry THF (20 mL) -3-one Int-9-4 (200 mg, 492 μmol) and 2-bromo-4-fluorobenzo [d] thiazole-6-carbonitrile Int-6-1 (190 mg, 738 μmol) in n-BuLi (in hexane 1.6M; 0.6 mL, 984 μmol) was added at −78 ° C. under N ₂ . The mixture was stirred at −78 ° C. for 1 h, quenched with NH ₄ Cl (saturated) and extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with brine (2 × 20 mL), dried over Na ₂ SO ₄ , concentrated and purified by preparative TLC (EtOAc / DCM = 1: 30) to elute first eluting isomer 2 -((1R, 5S) -8-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -3-hydroxybicyclo [3.2.1] octane-3 -Yl) -4-fluorobenzo [d] thiazole-6-carbonitrile 40 and the second eluting isomer 2-((1R, 5S) -8-((5-cyclopropyl-3- (2,6 -Dichlorophenyl) isoxazol-4-yl) methoxy) -3-hydroxybicyclo [3.2.1] octane-3-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile 4 It was obtained. LCMS (ESI): m / z 584.0 (M + H) ^<+> , 608.0 (M + Na) ^<+> .

(Example 42)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) benzo [d] thiazole-6-carbaldehyde

Step 1: 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) in THF / MeOH (4/2 mL) ) A solution of methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole-6-carboxylic acid 11-22 (200 mg, 0.34 mmol) was cooled to 0 ° C. TMSCHN ₂ (2.0 M in hexane, 0.26 mL, 0.51 mmol) was added dropwise over 5 minutes under Ar atmosphere. The resulting solution was stirred at room temperature for 2 hours and the reaction was quenched with dilute AcOH (0.5N). The mixture was extracted with EtOAc (3 × 10 mL) and the organic layers were combined, washed with brine (2 × 10 mL), dried over Na ₂ SO ₄ and concentrated. Crude methyl 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3 2.1] octane-8-yl) benzo [d] thiazole-6-carboxylate (200 mg) was used in the next step without further purification.

Step 2: Crude methyl 2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) in MeOH (5 mL). A solution of methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole-6-carboxylate (200 mg) was cooled to 0 ° C. and NaBH ₄ (27 mg, 0.7 mmol). ) Was added in several portions over 10 minutes under Ar atmosphere. The resulting solution was stirred at room temperature for 2 hours and the reaction was quenched with NH ₄ Cl (saturated aqueous solution). The mixture was extracted with EtOAc (3 × 10 mL) and the organic layers were combined, washed with brine (2 × 10 mL), dried over Na ₂ SO ₄ and concentrated. Crude (1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8- (6- (hydroxymethyl) benzo [D] thiazol-2-yl) bicyclo [3.2.1] octan-8-ol (100 mg) was used in the next step without further purification.

Step 3: Crude (1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8 in DCM (3 mL) Activated MnO ₂ (76 mg, 0.88 mmol) in a solution of-(6- (hydroxymethyl) benzo [d] thiazol-2-yl) bicyclo [3.2.1] octan-8-ol (100 mg) And the resulting dark black suspension was stirred at room temperature for 1 hour. The mixture was filtered off through a pad of celite, the filtrate was concentrated to dryness and the residue was purified by flash column chromatography on silica gel to give 2-((1R, 3s, 5S, 8r) -3-((5 -Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) benzo [d] thiazole-6-carbaldehyde 42 was obtained.

(Example 43)
(1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8- (6- (morpholinomethyl) benzo [d ] Thiazol-2-yl) bicyclo [3.2.1] octane-8-ol

2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy in MeOH (2 mL) To a solution of bicyclo [3.2.1] octane-8-yl) benzo [d] thiazole-6-carbaldehyde 42 (70 mg, 0.12 mmol) was added Ti (OiPr) ₄ (70 mg, 0.24 mmol) and morpholine. (21 mg, 0.24 mmol) was added at room temperature and the resulting mixture was stirred overnight. NaBH ₄ (10 mg, 0.24 mmol) was added in several portions at 0 ° C. under Ar atmosphere. The resulting solution was stirred at room temperature for an additional 2 hours and the reaction was quenched with NH ₄ Cl (saturated aqueous solution). The mixture was extracted with EtOAc (3 × 10 mL) and the organic layers were combined, washed with brine (2 × 10 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to give (1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8. ¹ H-NMR (400 MHz, DMSO-d ₆ ) giving-(6- (morpholinomethyl) benzo- [d] thiazol-2-yl) bicyclo [3.2.1] octan-8-ol 43 : δ 7.96 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.67-7.56 (m, 3H), 7.41 (d, J = 7.6 Hz, 1H), 6.23 (s, 1H), 4.28 (s, 2H), 3.57 (s, 6H), 3.58-3.47 (m, 1H), 2.39-2.32 (m, 7H), 1.86-1.81 (m, 2H), 1.75-1.70 (m, 2H), 1.65 -1.65 (m, 2H), 1.42-1.34 (m, 2H), 1.19-1.07 (m, 4H). LC / MS (ESI): m / z 639.8 (M + H) ⁺ .

(Example 44)
Ethyl 2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [ 3.2.1] Octane-8-yl) -5- (trifluoromethyl) oxazol-4-yl) acetate

Ethyl 2- (5- (trifluoromethyl) oxazol-4-yl) acetate Int-6-12 (200 mg, 0.9 mmol) and (1R, 3s, 5S) -3-(( 5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-one (Int-4-14a) (243 mg, 0.6 mmol) Was cooled to −78 ° C. in a dry ice / acetone bath and then n-BuLi (1.5 M in THF, 0.6 mL, 0.9 mmol) was added dropwise over 10 min under Ar atmosphere. The resulting solution was stirred at −78 ° C. for 2 h and the reaction was quenched with NH ₄ Cl (saturated aqueous solution). The reaction mixture was extracted with EtOAc (3 × 10 mL) and the organic layers were combined, washed with brine (2 × 10 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to obtain ethyl 2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl). ) Isooxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -5- (trifluoromethyl) oxazol-4-yl) acetate 44 was obtained.

(Example 45)
2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3 2.1] octane-8-yl) -5- (trifluoromethyl) oxazol-4-yl) acetic acid

Ethyl 2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) in MeOH (5 mL) To a solution of -8-hydroxybicyclo [3.2.1] octane-8-yl) -5- (trifluoromethyl) oxazol-4-yl) acetate 44 (70 mg, 0.11 mmol), LiOH (1 N, aqueous solution). 0.25 mL) and the resulting mixture was stirred at room temperature for an additional 4 hours. The solvent was removed under reduced pressure and the pH was adjusted to pH = 4-5 with dilute HCl (0.5N, aqueous solution). The residue was extracted with EtOAc (3 × 5 mL) and the organic layers were combined, dried over Na ₂ SO ₄ and then concentrated under reduced pressure. The residue was purified by preparative TLC to give 2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4 -Yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -5- (trifluoromethyl) -oxazol-4-yl) acetic acid 45. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.98 (br s, 1H), 7.67-7.54 (m, 3H), 6.18 (s, 1H), 4.26 (s, 2H), 3.62 (s, 2H), 3.48-3.36 (m, 1H), 2.42-2.31 (m, 3H), 1.72 (t, J = 11.2 Hz, 2H), 1.58-1.54 (m, 2H), 1.46-1.22 (m, 4H) , 1.19-1.09 (m, 4H). ¹⁹ F-NMR (376 MHz, DMSO-d ₆ ): δ-60.95. LC / MS (ESI): m / z 600.9 (M ⁺ H) ⁺ .

(Example 46)
2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3 2.1] Octane-8-yl) thiazol-4-yl) acetic acid

(1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8 in MeCN (10 mL) and water (3 mL) To a solution of-(4- (2-hydroxyethyl) thiazol-2-yl) bicyclo [3.2.1] octane-8-ol (9-30, 85 mg, 0.16 mmol) was added TEMPO (4N, 2 mL). And iodobenzene diacetate (100 mg, 0.11 mmol) were added and the mixture was stirred at room temperature for 1 h, diluted with water and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), concentrated and purified by preparative HPLC to give compound 2- (2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl- 3- (2,6-Dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) thiazol-4-yl) acetic acid 46 was obtained. ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 7.65-7.64 (m, 2H), 7.59-7.55 (m, 1H), 7.25 (s, 1H), 5.90 (s, 1H), 4.26 (s , 2H), 3.47-3.41 (m, 3H), 2.37-2.33 (m, 1H), 2.25 (s, 2H), 1.80-1.76 (m, 2H), 1.62-1.52 (m, 4H), 1.30-1.28 (m, 2H), 1.16-1.08 (m, 4H), CO ₂ H protons are not split. LCMS (ESI): m / z 549 (M + H) ^<+> .

(Example 47)
2-((1R, 3s, 5S, 8r) -3-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -8-hydroxybicyclo [3. 2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid

In a sealed tube, NaOH (40% aqueous solution, 1.0 mL) was replaced with 2-((1R, 3s, 5S, 8r) -3-((4-cyclopropyl-1- (2,6-dichlorophenyl) -1H-pyrazole). -5-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (8-16, 200 mg, 0.34 mmol) Added to. The vial was sealed, heated to 80 ° C. overnight, concentrated and purified by preparative TLC to give 2-((1R, 3s, 5S, 8r) -3-((4-cyclopropyl-1- (2, 6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxylic acid 47 I let you. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 13.43 (br s, 1H), 8.53 (s, 1H), 7.77-7.66 (m, 3H), 7.59 (t, J = 8.0 Hz, 1H) , 7.43 (s, 1H), 6.52 (s, 1H), 4.39 (s, 2H), 3.53-3.45 (m, 1H), 2.36-2.32 (m, 2H), 1.83-1.75 (m, 5H), 1.66 -1.60 (m, 2H), 1.44-1.39 (m, 2H), 0.94-0.89 (m, 2H), 0.66-0.62 (m, 2H). ¹⁹ F-NMR (376 MHz, DMSO-d ₆ ): δ -122.53. LC / MS (ESI) ^: m / z 601.8 (M ⁺ H) ^<+> .

(Example 48)
2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2. 1] Octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxamide

2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy in DMSO (5 mL) To a solution of bicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carbonitrile (8-9, 200 mg, 0.34 mmol) was added H ₂ O ₂ (1 mL). Was added dropwise. The mixture was stirred at room temperature for 2 hours, poured into water (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), concentrated and purified by column chromatography (EtOAc / PE = 1: 3) to give compound 2-((1R, 3s, 5S, 8r) -3- ( (5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxybicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] Thiazole-6-carboxamide 48 was obtained.

(Example 49)
(1R, 3s, 5S, 8r) -8- (6- (Aminomethyl) -4-fluorobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2,6- Dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2.1] octan-8-ol

  2-((1R, 3s, 5S, 8r) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-hydroxy in THF (20 mL) To a solution of bicyclo [3.2.1] octane-8-yl) -4-fluorobenzo [d] thiazole-6-carboxamide 48 (150 mg, 0.25 mmol) was added 1 N LAH (1 mL) dropwise. The mixture was stirred at room temperature overnight, poured into water (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), concentrated and purified by column chromatography (EtOAc / PE = 1: 1) to give (1R, 3s, 5S, 8r) -8- (6- (amino Methyl) -4-fluorobenzo [d] thiazol-2-yl) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) bicyclo [3.2. 1] Octane-8-ol 49 was obtained.

Assay FRET activity assay Determination of ligand-mediated cofactor peptide interaction to quantify ligand binding to the nuclear receptor FXR was performed as follows: Preparation of human FXRalpha ligand binding domain: human FXRalpha LBD And expressed as an N-terminal GST-tagged fusion protein in E. coli strain BL21 (DE3). DNA encoding the FXR ligand binding domain was cloned into the vector pDEST15 (Invitrogen). Expression was under the control of the IPTG inducible T7 promoter. The amino acid boundary of the ligand binding domain was amino acids 187-472 in database entry NM_005123 (RefSeq). FXR-LBD Expression and Purification: An overnight preculture of transformed E. coli strain was diluted 1:20 in LB-ampicillin medium and grown at 30 ° C. to give OD ₆₀₀ = 0.4-0.6 Optical density was set. Gene expression was then induced by the addition of 0.5 mM IPTG. Cells were incubated for an additional 6 hours at 30 ° C. and 180 rpm. Cells were collected by centrifugation (7000 × g, 7 minutes, room temperature). Cells were resuspended in 10 mL lysis buffer (50 mM glucose, 50 mM Tris pH 7.9, 1 mM EDTA and 4 mg / mL lysozyme) per liter of original cell culture and left on ice for 30 minutes. The cells were then sonicated and cell debris was removed via centrifugation (22000 × g, 30 min, 4 ° C.). 0.5 mL of pre-washed glutathione 4B Sepharose slurry (Qiagen) per 10 mL of supernatant was added and the suspension was slowly rotated at 4 ° C. for 1 hour. Glutathione 4B sepharose beads were pelleted by centrifugation (2000 × g, 15 seconds, 4 ° C.) and washed twice with wash buffer (25 mM Tris, 50 mM KCl, 4 mM MgCl ₂ and 1 M NaCl). The pellet was resuspended in 3 mL elution buffer per liter of original culture (elution buffer: 20 mM Tris, 60 mM KCl, 5 mM MgCl ₂ and 80 mM glutathione added as a powder just prior to use). The suspension was left to rotate at 4 ° C. for 15 minutes, the beads were pelleted and re-eluted with half volume of elution buffer for the first time. The eluates were pooled and dialyzed overnight in 20 mM Hepes buffer (pH 7.5) containing 60 mM KCl, 5 mM MgCl ₂ and 1 mM dithiothreitol and 10% (v / v) glycerol. Protein was analyzed by SDS-Page.

The method modulates the interaction between purified bacterially expressed FXR ligand binding domain (LBD) and a synthetic biotinylated peptide based on residues 676-700 of SRC-1 (LCD2, 676-700) Measure the estimated ligand capacity. The sequence of the peptide used was B-CPSSHSSLTERHKILHRLLQEGSPS-COOH, where the N-terminus was biotinylated (B). The ligand binding domain (LBD) of FXR was expressed as a fusion protein with GST in BL-21 cells using the vector pDEST15. Cells were lysed by sonication and the fusion protein was purified with glutathione sepharose (Pharmacia) according to the manufacturer's instructions. Perkin Elmer LANCE technology was applied to screen compounds for these effects on FXR-peptide interactions. This method relies on binding-dependent energy transfer from the donor to the acceptor phosphor bound to the binding partner of interest. To simplify handling and reduce background from compound fluorescence, LANCE technology utilizes generic phosphor labels and time-resolved detection assays are recombinant expression condensed to 20-60 ng / well GST. FXR-LBD, 200-600 nM, N-terminal biotinylated peptide showing SRC1 amino acids 676-700, 200 ng / well streptavidin-xlAPC conjugate (Prozyme) and 6-10 ng / well Eu W1024-anti-GST ( Perkin Elmer) in Tris-based buffer (20 mM Tris-HCl pH 7.5; 60 mM KCl, 5 mM MgCl ₂ ; 35 ng / μL BSA) in a 384 well plate with a final volume of 25 μL. The DMSO content of the sample was kept at 1%. After generating the assay mix and diluting the potential FXR modulating ligand, the assay was allowed to equilibrate for 1 hour at room temperature in the dark in a FIA plate black 384 well (Greiner). The LANCE signal was detected with a Perkin Elmer Victor2VTM multilabel counter. Results were visualized by plotting the ratio between the emitted light at 665 and 615 nm. The basal level of FXR-peptide formation was observed in the absence of added ligand. Ligands that promote complex formation induce a concentration-dependent increase in time-resolved fluorescent signal. Compounds that bind equally well to both monomeric FXR and FXR-peptide complexes are expected not to alter the signal, whereas ligands that selectively bind to the monomeric receptor are observed. It is expected to induce a concentration-dependent reduction in signal.

In order to evaluate the agonist potency of the compounds, EC ₅₀ values were determined for the example compounds as listed in Table 1 below (F EC ₅₀ ).

Mammalian One-Hybrid (M1H) Assay To quantify ligand binding-mediated activation of FXR, the determination of transactivation driven by a ligand-mediated Gal4 promoter was performed as follows: The coding cDNA portion was cloned into the vector pCMV-BD (Stratagene) as a fusion to the yeast GAL4 DNA binding domain under the control of the CMV promoter. The amino acid boundary of the ligand binding domain was amino acids 187-472 in database entry NM_005123 (RefSeq). Plasmid pFR-Luc (Stratagene), containing a synthetic promoter with five tandem repeats of the yeast GAL4 binding site, was used as a reporter plasmid to drive the expression of the Photinus pyralis (Kitaamerica firefly) luciferase gene as a reporter gene. . To improve experimental accuracy, plasmid pRL-CMV (Promega) was cotransfected. pRL-CMV contains a constitutive CMV promoter that controls the expression of Renilla reniformis luciferase. All Gal4 reporter gene assays have L-glutamine and Earle's BSS supplemented with 10% fetal bovine serum, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, and 100 units penicillin / streptavidin per mL HEK293 cells (obtained from DSMZ, Braunschweig, Germany) grown in MEM at 37 ° C., 5% CO ₂ . Media and supplements were obtained from Invitrogen. For the assay, 5 × 10 ⁵ cells per well in a 96 well plate were treated with 10% charcoal / dextran treated FBS (HyClone, South Logan, Utah), 0, without phenol red and L-glutamine. Plate in 100 μL MEM per well containing 1 mM non-essential amino acids, 2 mM glutamine, 1 mM sodium pyruvate, and Earle's BSS supplemented with 100 units penicillin / streptavidin per mL, 37 ° C., 5% It was incubated in CO _2. The next day, the cells were> 90% confluent. Media removed and 20 μL OptiMEM-polyethylene-imine based transfection reagent (OptiMEM, Invitrogen; Polyethyleneimine, Aldrich Cat No. 40, 827-7) per well containing the three plasmids described above. ) Were used to transiently transfect cells. MEM having the same composition used to plate the cells was added 2-4 hours after the addition of the transfection mixture. Compound stock pre-diluted in MEM was then added (final vehicle concentration does not exceed 0.1%). Cells were incubated for an additional 16 hours, after which firefly and Renilla luciferase activity was measured sequentially in the same cell extract using the Dual-Light-Luciferase-assay system (Dyer et al., Anal. Biochem., 2000). Year, 282, 158-161). All experiments were performed in duplicate.

To assess the FXR agonist potency of the example compounds, efficacy was determined with the M1H assay as listed in Table 1 below (M EC ₅₀ ).

［式中、
Ｒは、水素、ハロゲン、Ｃ _１〜６ −アルキル、Ｃ _２〜６ −アルケニル、Ｃ _２〜６ −アルキニル、ハロ−Ｃ _１〜６ −アルキル、Ｃ _０〜６ −アルキレン−Ｒ ^７ 、Ｃ _０〜６ −アルキレン−Ｏ−Ｒ ^７ 、Ｃ _０〜６ −アルキレン−ＣＮ、Ｃ _０〜６ −アルキレン−ＮＲ ^７ Ｒ ^８ 、Ｏ−Ｃ _３〜１０ −シクロアルキル、Ｏ−Ｃ _１〜６ −アルキレン−Ｏ−Ｒ ^７ 、Ｏ−Ｃ _３〜１０ −ヘテロシクロアルキル、Ｃ _０〜６ −アルキレン−ＣＯ _２ Ｒ ^７ 、Ｃ _０〜６ −アルキレン−Ｃ（Ｏ）Ｒ ^７ 、Ｃ _０〜６ −アルキレン−Ｃ（Ｏ）ＮＲ ^７ Ｒ ^８ 、Ｃ _０〜６ −アルキレン−Ｃ（Ｏ）ＮＲ ^７ ＳＯ _２ Ｒ ^７ 、Ｃ _０〜６ −アルキレン−Ｎ（Ｒ ^７ ）Ｃ（Ｏ）Ｒ ^７ 、Ｃ _０〜６ −アルキレン−ＳＯ _ｘ −Ｒ ^７ 、Ｃ _０〜６ −アルキレン−ＳＯ _３ Ｈ、Ｃ _０〜６ −アルキレン−ＳＯ _２ −ＮＲ ^７ Ｒ ^８ 、Ｃ _０〜６ −アルキレン−ＳＯ _２ −ＮＲ ^８ ＣＯＲ ^７ 、Ｃ _０〜６ −アルキレン−Ｎ（Ｒ ^７ ）ＳＯ _２ −Ｒ ^８ 、およびＣ _０〜６ −アルキレン−ＳＯ _２ −Ｃ _３〜１０ −ヘテロシクロアルキルからなる群から選択され、
ここで、アルキレン、シクロアルキル、ヘテロシクロアルキルおよび５または６員のヘテロアリールは、非置換であるか、またはハロゲン、ＣＮ、Ｃ _１〜３ −アルキル、ハロ−Ｃ _１〜３ −アルキル、ＯＨ、オキソ、ＣＯ _２ Ｈ、ＳＯ _３ Ｈ、Ｏ−Ｃ _１〜３ −アルキルおよびＯ−ハロ−Ｃ _１〜３ −アルキルからなる群から独立に選択される１から４個の置換基によって置換されており、
Ｒ ^７ は、水素、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキル、Ｃ _０〜６ −アルキレン−Ｃ _３〜８ −シクロアルキル、Ｃ _０〜６ −アルキレン−Ｃ _３〜８ −ヘテロシクロアルキル、５または６員のヘテロアリールおよびフェニルからなる群から独立に選択され、ここで、アルキル、アルキレン、シクロアルキル、ヘテロシクロアルキル、フェニルおよびヘテロアリールは、非置換であるか、またはハロゲン、ＣＮ、ＯＨ、オキソ、ＣＯ _２ Ｈ、Ｃ _１〜３ −アルキル、ハロ−Ｃ _１〜３ −アルキル、Ｏ−Ｃ _１〜３ −アルキル、Ｏ−ハロ−Ｃ _１〜３ −アルキル、ＳＯ _３ ＨおよびＳＯ _２ −Ｃ _１〜３ −アルキルからなる群から独立に選択される１から６個の置換基で置換されており、
Ｒ ^８ は、水素、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキルおよびＣ _３〜６ −シクロアルキルからなる群から独立に選択されるか、
あるいは、Ｒ ^７ およびＲ ^８ は、それらが結合している窒素と一緒になると、炭素原子を含有し、かつＯ、ＳまたはＮから選択される１または２個のヘテロ原子を任意選択で含有する３から８員の環を完成させてよく、ここで、前記環は、非置換であるか、またはフルオロ、ＯＨ、オキソ、Ｃ _１〜４ −アルキルおよびハロ−Ｃ _１〜４ −アルキルからなる群から独立に選択される１から４個の置換基で置換されており、
Ａは、６〜１０員の単環式もしくは二環式アリール、またはＮ、ＯおよびＳからなる群から独立に選択される１から５個のヘテロ原子を含有する５〜１０員の単環式もしくは二環式ヘテロアリールであり、ここで、アリールおよびヘテロアリールは、非置換であるか、またはＯＨ、ハロゲン、ＣＮ、Ｏ−Ｃ _１〜６ −アルキル、Ｏ−ハロ−Ｃ _１〜６ −アルキル、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキル、Ｃ _３〜６ −シクロアルキル、Ｃ _５〜６ −ヘテロシクロアルキルおよびハロ−Ｃ _３〜６ −シクロアルキルからなる群から独立に選択される１または２個の基で置換されており、
Ｑは、Ｃ _３〜１０ −シクロアルキル環、またはＣ _５〜１０ −架橋シクロアルキル環であり、−Ｏ−ＣＨ _２ −Ｚ−置換基は、置換基Ａに直接隣接しておらず、Ｑが二環式または多環式環系である場合、炭素原子は、酸素、ＳＯ _ｘ またはＮＲ ^７ で、任意選択で置き換えられていてもよく、
Ｚは、

から選択され
式中、
Ｌは、結合、Ｃ _１〜３ −アルキレンおよびＣ _１〜３ −アルキレン−Ｏ−からなる群から選択され、
Ｙは、フェニル、ピリジル、ピリジル−Ｎ−オキシド、ピリミジル、ピリジノニル、ピリミジノニル、Ｃ _４〜８ −シクロアルキルおよびＣ _４〜８ −ヘテロシクロアルキルからなる群から選択され、ここで、フェニル、ピリジル、ピリジル−Ｎ−オキシド、ピリミジル、ピリジノニル、ピリミジノニル、Ｃ _４〜８ −シクロアルキルおよびＣ _４〜８ −ヘテロシクロアルキルは、Ｒ ^２ およびＲ ^３ で置換されており、フルオロ、クロロ、ＣＮ、ＮＨ _２ 、ＮＨ（Ｃ _１〜３ −アルキル）、Ｎ（Ｃ _１〜３ −アルキル） _２ 、Ｃ _１〜３ −アルキル、フルオロ−Ｃ _１〜３ −アルキル、ＯＨ、Ｃ _１〜３ −アルコキシ、フルオロ−Ｃ _１〜３ −アルコキシ、Ｃ _３〜６ −シクロアルキルおよびフルオロ−Ｃ _３〜６ −シクロアルキルから選択される基で１または２回、任意選択で置換されており、
Ｒ ^１ は、Ｃ _１〜４ −アルキルおよびＣ _３〜６ −シクロアルキルからなる群から選択され、ここで、Ｃ _１〜４ −アルキルは、非置換であるか、またはフルオロ、ヒドロキシ、Ｃ _１〜３ −アルコキシおよびフルオロ−Ｃ _１〜３ −アルコキシからなる群から独立に選択される１から３個の置換基で置換されており、そしてＣ _３〜６ −シクロアルキルは非置換であるか、またはフルオロ、ヒドロキシ、Ｃ _１〜３ −アルキル、フルオロ−Ｃ _１〜３ −アルキル、Ｃ _１〜３ −アルコキシおよびフルオロ−Ｃ _１〜３ −アルコキシからなる群から独立に選択される１から３個の置換基で置換されており、
Ｒ ^２ およびＲ ^３ は、水素、ハロゲン、Ｃ _１〜３ −アルキル、ハロ−Ｃ _１〜３ −アルキル、Ｃ _１〜３ −アルコキシ、ハロ−Ｃ _１〜３ −アルコキシ、シクロプロピルおよびフルオロ−シクロプロピルからなる群から独立に選択され、
Ｒ ^４ は、ハロゲン、Ｃ _１〜３ −アルキル、ハロ−Ｃ _１〜３ −アルキル、Ｃ _１〜３ −アルコキシ、ハロ−Ｃ _１〜３ −アルコキシ、Ｃ _３〜６ −シクロアルキル、Ｃ _１〜３ −アルキレン−Ｏ−Ｃ _１〜３ −アルキルおよびフルオロ−Ｃ _３〜６ −シクロアルキルからなる群から独立に選択され、
Ｒ ^５ は、水素、フルオロ、ＣＨ _３ 、ＣＨＦ _２ およびＣＦ _３ からなる群から選択され、
ｎは、０、１、２、３および４から選択され、
ｘは、０、１および２から独立に選択される］。
（項目２）
下記の式（１）による化合物、そのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、プロドラッグまたは薬学的に許容される塩

［式中、
Ｒは、水素、ハロゲン、Ｃ _１〜６ −アルキル、Ｃ _２〜６ −アルケニル、Ｃ _２〜６ −アルキニル、ハロ−Ｃ _１〜６ −アルキル、Ｃ _０〜６ −アルキレン−Ｏ−Ｒ ^７ 、Ｃ _０〜６ −アルキレン−ＣＮ、Ｃ _０〜６ −アルキレン−ＮＲ ^７ Ｒ ^８ 、Ｏ−Ｃ _３〜１０ −シクロアルキル、Ｏ−Ｃ _１〜６ −アルキレン−Ｏ−Ｒ ^７ 、Ｏ−Ｃ _３〜１０ −ヘテロシクロアルキル、Ｃ _０〜６ −アルキレン−ＣＯ _２ Ｒ ^７ 、Ｃ _０〜６ −アルキレン−Ｃ（Ｏ）Ｒ ^７ 、Ｃ _０〜６ −アルキレン−Ｃ（Ｏ）ＮＲ ^７ Ｒ ^８ 、Ｃ _０〜６ −アルキレン−Ｃ（Ｏ）ＮＲ ^７ ＳＯ _２ Ｒ ^７ 、Ｃ _０〜６ −アルキレン−Ｎ（Ｒ ^７ ）Ｃ（Ｏ）Ｒ ^７ 、Ｃ _０〜６ −アルキレン−ＳＯ _ｘ −Ｒ ^７ 、Ｃ _０〜６ −アルキレン−ＳＯ _３ Ｈ、Ｃ _０〜６ −アルキレン−ＳＯ _２ −ＮＲ ^７ Ｒ ^８ 、Ｃ _０〜６ −アルキレン−ＳＯ _２ −ＮＲ ^８ ＣＯＲ ^７ 、Ｃ _０〜６ −アルキレン−Ｎ（Ｒ ^７ ）ＳＯ _２ −Ｒ ^８ 、およびＣ _０〜６ −アルキレン−ＳＯ _２ −Ｃ _３〜１０ −ヘテロシクロアルキルからなる群から選択され、
ここで、アルキレン、シクロアルキル、ヘテロシクロアルキルおよび５または６員のヘテロアリールは、非置換であるか、またはハロゲン、ＣＮ、Ｃ _１〜３ −アルキル、ハロ−Ｃ _１〜３ −アルキル、ＯＨ、オキソ、ＣＯ _２ Ｈ、ＳＯ _３ Ｈ、Ｏ−Ｃ _１〜３ −アルキルおよびＯ−ハロ−Ｃ _１〜３ −アルキルからなる群から独立に選択される１から４個の置換基によって置換されており、
Ｒ ^７ は、水素、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキル、Ｃ _０〜６ −アルキレン−Ｃ _３〜８ −シクロアルキル、Ｃ _０〜６ −アルキレン−Ｃ _３〜８ −ヘテロシクロアルキル、５または６員のヘテロアリールおよびフェニルからなる群から独立に選択され、ここで、アルキル、アルキレン、シクロアルキル、ヘテロシクロアルキル、フェニルおよびヘテロアリールは、非置換であるか、またはハロゲン、ＣＮ、ＯＨ、オキソ、ＣＯ _２ Ｈ、Ｃ _１〜３ −アルキル、ハロ−Ｃ _１〜３ −アルキル、Ｏ−Ｃ _１〜３ −アルキル、Ｏ−ハロ−Ｃ _１〜３ −アルキル、ＳＯ _３ ＨおよびＳＯ _２ −Ｃ _１〜３ −アルキルからなる群から独立に選択される１から６個の置換基で置換されており、
Ｒ ^８ は、水素、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキルおよびＣ _３〜６ −シクロアルキルからなる群から独立に選択されるか、
あるいは、Ｒ ^７ およびＲ ^８ は、それらが結合している窒素と一緒になると、炭素原子を含有し、かつＯ、ＳまたはＮから選択される１または２個のヘテロ原子を任意選択で含有する３から８員の環を完成させてよく、ここで、前記環は、非置換であるか、またはフルオロ、ＯＨ、オキソ、Ｃ _１〜４ −アルキルおよびハロ−Ｃ _１〜４ −アルキルからなる群から独立に選択される１から４個の置換基で置換されており、
Ａは、６〜１０員の単環式もしくは二環式アリール、またはＮ、ＯおよびＳからなる群から独立に選択される１から５個のヘテロ原子を含有する５〜１０員の単環式もしくは二環式ヘテロアリールであり、ここで、アリールおよびヘテロアリールは、非置換であるか、またはＯＨ、ハロゲン、ＣＮ、Ｏ−Ｃ _１〜６ −アルキル、Ｏ−ハロ−Ｃ _１〜６ −アルキル、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキル、Ｃ _３〜６ −シクロアルキルおよびハロ−Ｃ _３〜６ −シクロアルキルからなる群から独立に選択される１または２個の基で置換されており、
Ｑは、Ｃ _５〜８ −シクロアルキル環であり、−Ｏ−ＣＨ _２ −Ｚ−置換基は、置換基Ａに直接隣接しておらず、
Ｚは、

から選択され
式中、
Ｌは、結合、Ｃ _１〜３ −アルキレンおよびＣ _１〜３ −アルキレン−Ｏ−からなる群から選択され、
Ｙは、フェニル、ピリジル、ピリジル−Ｎ−オキシド、ピリミジル、ピリジノニル、ピリミジノニル、Ｃ _４〜８ −シクロアルキルおよびＣ _４〜８ −ヘテロシクロアルキルからなる群から選択され、ここで、フェニル、ピリジル、ピリジル−Ｎ−オキシド、ピリミジル、ピリジノニル、ピリミジノニル、Ｃ _４〜８ −シクロアルキルおよびＣ _４〜８ −ヘテロシクロアルキルは、Ｒ ^２ およびＲ ^３ で置換されており、フルオロ、クロロ、ＣＮ、ＮＨ _２ 、ＮＨ（Ｃ _１〜３ −アルキル）、Ｎ（Ｃ _１〜３ −アルキル） _２ 、Ｃ _１〜３ −アルキル、フルオロ−Ｃ _１〜３ −アルキル、ＯＨ、Ｃ _１〜３ −アルコキシ、フルオロ−Ｃ _１〜３ −アルコキシ、Ｃ _３〜６ −シクロアルキルおよびフルオロ−Ｃ _３〜６ −シクロアルキルから選択される基で１または２回、任意選択で置換されており、
Ｒ ^１ は、Ｃ _１〜４ −アルキルおよびＣ _３〜６ −シクロアルキルからなる群から選択され、ここで、Ｃ _１〜４ −アルキルは、非置換であるか、またはフルオロ、ヒドロキシ、Ｃ _１〜３ −アルコキシおよびフルオロ−Ｃ _１〜３ −アルコキシからなる群から独立に選択される１から３個の置換基で置換されており、そしてＣ _３〜６ −シクロアルキルは非置換であるか、またはフルオロ、ヒドロキシ、Ｃ _１〜３ −アルキル、フルオロ−Ｃ _１〜３ −アルキル、Ｃ _１〜３ −アルコキシおよびフルオロ−Ｃ _１〜３ −アルコキシからなる群から独立に選択される１から３個の置換基で置換されており、
Ｒ ^２ およびＲ ^３ は、水素、ハロゲン、Ｃ _１〜３ −アルキル、ハロ−Ｃ _１〜３ −アルキル、Ｃ _１〜３ −アルコキシ、ハロ−Ｃ _１〜３ −アルコキシ、シクロプロピルおよびフルオロ−シクロプロピルからなる群から独立に選択され、
Ｒ ^４ は、ハロゲン、Ｃ _１〜３ −アルキル、ハロ−Ｃ _１〜３ −アルキル、Ｃ _１〜３ −アルコキシ、ハロ−Ｃ _１〜３ −アルコキシ、Ｃ _３〜６ −シクロアルキルおよびフルオロ−Ｃ _３〜６ −シクロアルキルからなる群から独立に選択され、
Ｒ ^５ は、水素、フルオロ、ＣＨ _３ 、ＣＨＦ _２ およびＣＦ _３ からなる群から選択され、
ｎは、０、１、２、３および４から選択され、
ｘは、０、１および２から選択される］。
（項目３）
Ｒが、ＣＯ _２ Ｈ、ＳＯ _３ Ｈ、ＣＯＮＲ ^７ Ｒ ^８ 、テトラゾリル、１，２，４−オキサジアゾール−５（４Ｈ）−オン−３−イルおよびＳＯ _２ ＮＨＣＯＲ ^７ からなる群から選択され、
Ｒ ^７ が、水素、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキル、Ｃ _１〜６ −アルキレン−Ｒ ^９ およびＳＯ _２ −Ｃ _１〜３ −アルキルからなる群から選択され、
Ｒ ^８ が、水素、Ｃ _１〜６ −アルキルおよびハロ−Ｃ _１〜６ −アルキルからなる群から選択され、
Ｒ ^９ が、ＣＯＯＨ、ＯＨおよびＳＯ _３ Ｈからなる群から選択される、請求項１または２に記載の化合物。
（項目４）
Ａが、フェニル、ピリジル、ピリミジル、ピラゾリル、インドリル、チエニル、ベンゾチエニル、インダゾリル、ベンゾイソオキサゾリル、ベンゾイソチアゾリル、トリアゾロピリジニル、ベンゾフラニル、ベンゾトリアゾリル、フラニル、ベンゾチアゾリル、チアゾリル、オキサジアゾリル、オキサゾリル、ナフチル、キノリル、イソキノリル、ベンゾイミダゾリルからなる群から選択され、それぞれ、非置換であるか、またはＯＨ、ハロゲン、ＣＮ、Ｏ−Ｃ _１〜６ −アルキル、Ｏ−ハロ−Ｃ _１〜６ −アルキル、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキル、Ｃ _３〜６ −シクロアルキルおよびハロ−Ｃ _３〜６ −シクロアルキルからなる群から独立に選択される１もしくは２個の基で置換されている、請求項１から３のいずれかに記載の化合物。
（項目５）
Ａが、フェニル、ピリジル、インドリル、インダゾリル、ベンゾイソチアゾリル、トリアゾロピリジニル、ベンゾチアゾリル、チアゾリル、オキサゾリル、キノリルからなる群から選択され、それぞれ、非置換であるか、またはＯＨ、ハロゲン、ＣＮ、Ｏ−Ｃ _１〜６ −アルキル、Ｏ−ハロ−Ｃ _１〜６ −アルキル、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキル、Ｃ _３〜６ −シクロアルキルおよびハロ−Ｃ _３〜６ −シクロアルキルからなる群から独立に選択される１もしくは２個の基で置換されている、請求項４に記載の化合物。
（項目６）
Ｒ−Ａが、

から選択される、請求項１から５のいずれかに記載の化合物。
（項目７）
Ｚが、

から選択され、
式中、
Ｌは、結合、Ｃ _１〜３ −アルキレンおよびＣ _１〜３ −アルキレン−Ｏ−からなる群から選択され、
Ｘは、ＣＨ、ＣＦ、ＮおよびＮＯからなる群から選択され、
Ｒ ^１ は、Ｃ _１〜４ −アルキルおよびＣ _３〜６ −シクロアルキルからなる群から選択され、ここで、Ｃ _１〜４ −アルキルは、非置換であるか、またはフルオロ、ヒドロキシ、Ｃ _１〜３ −アルコキシおよびフルオロ−Ｃ _１〜３ −アルコキシからなる群から独立に選択される１から３個の置換基で置換されており、Ｃ _３〜６ −シクロアルキルは、非置換であるか、またはフルオロ、ヒドロキシ、Ｃ _１〜３ −アルキル、フルオロ−Ｃ _１〜３ −アルキル、Ｃ _１〜３ −アルコキシおよびフルオロ−Ｃ _１〜３ −アルコキシからなる群から独立に選択される１から３個の置換基で置換されており、
Ｒ ^２ およびＲ ^３ は、水素、ハロゲン、Ｃ _１〜３ −アルキル、ハロ−Ｃ _１〜３ −アルキル、Ｃ _１〜３ −アルコキシ、ハロ−Ｃ _１〜３ −アルコキシ、シクロプロピルおよびフルオロ−シクロプロピルからなる群から独立に選択され、
Ｒ ^５ は、水素、フルオロ、ＣＨ _３ 、ＣＨＦ _２ およびＣＦ _３ からなる群から選択される、請求項１から６のいずれかに記載の化合物。
（項目８）
Ｚが、

から選択され、
式中、
Ｘは、ＣＨ、ＣＦ、ＮおよびＮＯからなる群から選択され、
Ｒ ^１ は、メチル、ＣＦ _３ 、ＣＨＦ _２ 、イソプロピルおよびシクロプロピルからなる群から選択され、ここで、イソプロピルおよびシクロプロピルは、非置換であるか、あるいは１もしくは２個のフルオロまたは１個のヒドロキシで置換されており、
Ｒ ^２ は、フルオロ、クロロ、ＣＨ _３ 、ＣＨＦ _２ 、ＣＦ _３ 、ＯＣＨＦ _２ およびＯＣＦ _３ からなる群から選択され、
Ｒ ^３ は、水素、フルオロ、クロロ、ＣＨ _３ 、ＣＨＦ _２ 、ＣＦ _３ 、ＯＣＨＦ _２ およびＯＣＦ _３ からなる群から選択され、
Ｒ ^５ は、水素、フルオロ、ＣＨ _３ 、ＣＨＦ _２ およびＣＦ _３ からなる群から選択される、請求項１から７のいずれかに記載の化合物。
（項目９）

が、

から選択され、それぞれが、Ｒ ^４ で、任意選択で置換されている、請求項１から８のいずれかに記載の化合物。
（項目１０）
式（２）による、請求項１から９のいずれかに記載の化合物

［式中、
Ａは、フェニル、ピリジル、ピリミジル、ピラゾリル、インドリル、チエニル、ベンゾチエニル、インダゾリル、ベンゾイソオキサゾリル、ベンゾイソチアゾリル、トリアゾロピリジニル、ベンゾフラニル、ベンゾトリアゾリル、フラニル、ベンゾチアゾリル、チアゾリル、オキサジアゾリル、オキサゾリル、ナフチル、キノリル、イソキノリル、ベンゾイミダゾリルからなる群から選択され、それぞれ、非置換であるか、またはＯＨ、ハロゲン、ＣＮ、Ｏ−Ｃ _１〜６ −アルキル、Ｏ−ハロ−Ｃ _１〜６ −アルキル、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキル、Ｃ _３〜６ −シクロアルキルおよびハロ−Ｃ _３〜６ −シクロアルキルからなる群から独立に選択される１もしくは２個の基で置換されており、
Ｒは、ＣＯ _２ Ｈ、ＳＯ _３ Ｈ、ＣＯＮＲ ^７ Ｒ ^８ 、テトラゾリル、１，２，４−オキサジアゾール−５（４Ｈ）−オン−３−イルおよびＳＯ _２ ＮＨＣＯＲ ^７ からなる群から選択され、ここで、
Ｒ ^７ は、Ｈ、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキル、Ｃ _１〜６ −アルキレン−Ｒ ^９ およびＳＯ _２ −Ｃ _１〜６ −アルキルからなる群から選択され、
Ｒ ^８ は、Ｈ、Ｃ _１〜６ −アルキル、ハロ−Ｃ _１〜６ −アルキルからなる群から選択され、Ｒ ^９ は、ＣＯＯＨ、ＯＨおよびＳＯ _３ Ｈからなる群から選択され、
Ｚは、

から選択され、
Ｘは、ＣＨ、ＮおよびＮＯからなる群から選択され、
Ｒ ^１ は、メチル、イソプロピルおよびシクロプロピルからなる群から選択され、ここで、イソプロピルおよびシクロプロピルは、非置換であるか、あるいは１もしくは２個のフルオロまたは１個のヒドロキシで置換されており、
Ｒ ^２ は、フルオロ、クロロ、ＣＨ _３ 、ＣＨＦ _２ 、ＣＦ _３ 、ＯＣＨＦ _２ およびＯＣＦ _３ からなる群から選択され、
Ｒ ^３ は、水素、フルオロ、クロロ、ＣＨ _３ 、ＣＨＦ _２ 、ＣＦ _３ 、ＯＣＨＦ _２ およびＯＣＦ _３ からなる群から選択される］。
（項目１１）

からなる群から選択される化合物、またはそのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、プロドラッグもしくは薬学的に許容される塩。
（項目１２）
医薬としての、請求項１から１１のいずれかに記載の化合物。
（項目１３）
ＦＸＲによって媒介される疾患の予防および／または治療において使用するための、請求項１から１１のいずれかに記載の化合物。
（項目１４）
前記疾患が、
慢性的な肝内または一部の形態の肝外の胆汁うっ滞状態、
肝線維症、
肝臓の閉塞性または慢性炎症性障害、
肝硬変、
脂肪肝および関連症候群、アルコール誘導性肝硬変にまたは肝炎のウイルス媒介性形態に関連する胆汁うっ滞または線維化効果、
広範囲肝切除後の肝不全または肝虚血、
化学療法関連脂肪性肝炎（ＣＡＳＨ）；
急性肝不全、ならびに
炎症性腸疾患
から選択される、請求項１３に記載の使用のための化合物。
（項目１５）
前記疾患が、
脂質およびリポタンパク質障害、
ＩＩ型糖尿病、ならびに、糖尿病性腎症、糖尿病性神経障害、糖尿病性網膜症および臨床的に明確な長期糖尿病の観察される他の影響を含む、Ｉ型およびＩＩ型糖尿病の臨床的合併症、
脂質、具体的にはトリグリセリドの強制的な蓄積およびその後の線維化促進経路の活性化による臓器の慢性脂肪および線維性変性に起因する状態および疾患、例えば、非アルコール性脂肪肝疾患（ＮＡＦＬＤ）、または非アルコール性脂肪性肝炎（ＮＡＳＨ）など、
肥満またはメタボリックシンドローム（脂質異常症、糖尿病または異常に高いボディマス指数の複合的な状態）、ならびに
慢性閉塞性アテローム性動脈硬化症のエンドポイントとして発生する、急性心筋梗塞、急性脳卒中または血栓症
から選択される、請求項１３に記載の使用のための化合物。
（項目１６）
前記疾患が、非悪性過剰増殖性障害および悪性過剰増殖性障害、具体的には、肝細胞癌、結腸腺腫およびポリポーシス、結腸腺癌、乳がん、膵臓腺癌、バレット食道、または胃腸管および肝臓の新生物疾患の他の形態から選択される、請求項１３に記載の使用のための化合物。 Said problem is solved by FXR-agonists according to formula (1), which have higher physicochemical properties compared to known FXR-agonists. In particular, the introduction of a hydroxyl group at the carbon atom of moiety Q linked to moiety A is calculated between the calculated value of a known FXR-agonist having the relevant structure and the calculated clogP and tPSA of Example 4 of the present invention. As can be taken from FIG. 1, which shows the comparison, it leads to a decrease in clogP, an increase in topological polar surface area and thus an improvement in water solubility compared to the related structure disclosed in WO2012 / 087520. At the same time, the compounds of the invention maintain high activity on the FXR-receptor in both biochemical and cellular assays. More specifically, compounds of the present invention having a cis structure of two oxygen substituents in the central cyclic alkyl moiety Q have higher activity on the FXR receptor than those having a trans structure.
In the embodiment of the present invention, for example, the following items are provided.
(Item 1)
A compound according to the following formula (1), its enantiomer, diastereomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt

[Where:
R is hydrogen, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, halo-C _1-6 -alkyl, C _0-6 -alkylene-R ⁷ , C _{0- 6} -alkylene-O—R ⁷ , C _0-6 -alkylene-CN, C _0-6 -alkylene-NR ⁷ R ⁸ , O—C _3-10 -cycloalkyl, O—C _1-6 -alkylene-O -R ^7, _O-C 3~10 - _{heterocycloalkyl, C Less than six} - alkylene _-CO 2 ^R _{7, C 0~6} - alkylene ^{_{-C (O) R 7, C}} 0~6 - alkylene -C ( ^{_{O) NR 7 R 8, C}} 0~6 - alkylene ^{_{-C (O) NR 7 SO 2}} R 7, C 0~6 - alkylene ^{-N (R 7) C (O} ) R 7, C 0~6 - alkylene _{-SO x} -R ^7, _C 0~6 - alkylene _-SO 3 H, _{C 0 6} - alkylene ^{_{-SO 2 -NR 7 R 8, C}} 0~6 - alkylene ^{_{-SO 2 -NR 8 COR 7, C}} 0~6 - alkylene ^{_{-N (R 7) SO 2 -R}} 8, and _{C 0 to 6} - alkylene _-SO 2 _{-C 3 to 10} - is selected from the group consisting of heterocycloalkyl,
Where alkylene, cycloalkyl, heterocycloalkyl and 5- or 6-membered heteroaryl are unsubstituted or halogen, CN, C _1-3 -alkyl, halo-C _1-3 -alkyl, OH, _{oxo, CO 2 H, SO 3 H} , O-C 1~3 - is substituted by one to four substituents selected from the group consisting of alkyl independently - alkyl and O- halo _{-C 1 to 3} ,
R ⁷ is _{hydrogen, C 1 to 6} - alkyl, halo _{-C 1 to 6} - _{alkyl, C Less than six} - alkylene _{-C 3 to 8} - _{cycloalkyl, C Less than six} - alkylene _{-C 3 to 8} - hetero Independently selected from the group consisting of cycloalkyl, 5 or 6 membered heteroaryl and phenyl, wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are unsubstituted or halogen; CN, OH, _oxo, CO 2 _{H, C 1~3} - alkyl, halo _{-C 1 to 3} - alkyl, _{O-C 1 to 3} - alkyl, O- halo _{-C 1 to 3} - alkyl, SO ₃ H and Substituted with 1 to 6 substituents independently selected from the group consisting of SO ₂ -C _1-3 -alkyl,
R ⁸ is independently selected from the group consisting of hydrogen, C _1-6 -alkyl, halo-C _1-6 -alkyl and C _3-6 -cycloalkyl,
Alternatively, R ⁷ and R ⁸ together with the nitrogen to which they are attached contain a carbon atom and optionally contain 1 or 2 heteroatoms selected from O, S or N A 3- to 8-membered ring may be completed, wherein said ring is unsubstituted or grouped of fluoro, OH, oxo, C _1-4 -alkyl and halo-C _1-4 -alkyl Substituted with 1 to 4 substituents independently selected from
A is 6-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic containing 1-5 heteroatoms independently selected from the group consisting of N, O and S Or bicyclic heteroaryl, where aryl and heteroaryl are unsubstituted or OH, halogen, CN, O—C _1-6 -alkyl, O-halo-C _1-6 -alkyl Independently selected from the group consisting of C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-6 -cycloalkyl, C _5-6 -heterocycloalkyl and halo-C _3-6 -cycloalkyl Substituted with 1 or 2 groups
Q is a C _3-10 -cycloalkyl ring, or a C _{5-10 -bridged} cycloalkyl ring, and the —O—CH ₂ —Z-substituent is not directly adjacent to substituent A, and Q is When it is a bicyclic or polycyclic ring system, the carbon atom may be optionally replaced with oxygen, SO _x or NR ⁷ ,
Z is

Selected from
Where
L is selected from the group consisting of a bond, C _1-3 -alkylene and C _1-3 -alkylene-O—
Y is selected from the group consisting of phenyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C _4-8 -cycloalkyl and C _4-8 -heterocycloalkyl, wherein phenyl, pyridyl, pyridyl -N- oxide, pyrimidyl, pyridinonyl, _{pyrimidinonyl, C 4 to 8} - cycloalkyl and _{C 4 to 8} - heterocycloalkyl is substituted with ^{R 2} and ^{R 3,} fluoro, chloro, _CN, NH 2, NH (C _1-3 -alkyl), N (C _1-3 -alkyl) ₂ , C _1-3 -alkyl, fluoro-C _1-3 -alkyl, OH, C _1-3 -alkoxy, fluoro-C _{1- 3} - _{alkoxy, C 3 to 6} - cycloalkyl and fluoro _{-C 3 to 6} - with a group selected from cycloalkyl Or twice, it is optionally substituted,
R ¹ is selected from the group consisting of C _1-4 -alkyl and C _3-6 -cycloalkyl, wherein C _1-4 -alkyl is unsubstituted or fluoro, hydroxy, C _{1- 3} - alkoxy and fluoro -C _{1 to 3 -} are substituted with one to three substituents independently selected from the group consisting of alkoxy, and C _{3 to 6 -} or cycloalkyl is unsubstituted, or 1 to 3 substitutions independently selected from the group consisting of fluoro, hydroxy, C _1-3 -alkyl, fluoro-C _1-3 -alkyl, C _1-3 -alkoxy and fluoro-C _1-3 -alkoxy Substituted with a group,
R ² and R ³ are hydrogen, halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, cyclopropyl and fluoro-cyclopropyl Independently selected from the group consisting of
R ⁴ is halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, C _3-6 -cycloalkyl, C _1-3 Independently selected from the group consisting of -alkylene-O-C _1-3 -alkyl and fluoro-C _3-6 -cycloalkyl;
R ⁵ is selected from the group consisting of hydrogen, fluoro, CH ₃ , CHF ₂ and CF ₃ ;
n is selected from 0, 1, 2, 3 and 4;
x is independently selected from 0, 1 and 2.]
(Item 2)
A compound according to the following formula (1), its enantiomer, diastereomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt

[Where:
R is hydrogen, _{halogen, C 1 to 6} - _{alkyl, C 2 to 6} - _{alkenyl, C 2 to 6} - alkynyl, halo _{-C 1 to 6} - _{alkyl, C Less than six} - alkylene ^-O-R 7, C _0-6 - alkylene _{-CN, C 0-6} - alkylene ^{_{-NR 7 R 8, O-C}} 3~10 - cycloalkyl, _{O-C 1 to 6} - alkylene ^{_{-O-R 7, O-C}} 3~10 - _{heterocycloalkyl, C Less than six} - alkylene _-CO 2 ^R _{7, C 0~6} - alkylene ^{_{-C (O) R 7, C}} 0~6 - alkylene ^{-C (O) NR 7 R 8} , C 0~ ₆ - alkylene ^{_{-C (O) NR 7 SO 2}} R 7, C 0~6 - alkylene ^{-N (R 7) C (O} ) R 7, C 0~6 - alkylene _-SO x ^-R _{7, C 0~ 6} - alkylene _-SO 3 _{H, C 0~6} - alkylene _-SO 2 -N ⁷ R ^8, _{C 0~6} - alkylene ^{_{-SO 2 -NR 8 COR 7, C}} 0~6 - alkylene ^{_{-N (R 7) SO 2 -R}} 8, and _{C Less than six} - alkylene _-SO 2 -C ₃ Selected from the group consisting of ₁₀ -heterocycloalkyl,
Where alkylene, cycloalkyl, heterocycloalkyl and 5- or 6-membered heteroaryl are unsubstituted or halogen, CN, C _1-3 -alkyl, halo-C _1-3 -alkyl, OH, _{oxo, CO 2 H, SO 3 H} , O-C 1~3 - is substituted by one to four substituents selected from the group consisting of alkyl independently - alkyl and O- halo _{-C 1 to 3} ,
R ⁷ is _{hydrogen, C 1 to 6} - alkyl, halo _{-C 1 to 6} - _{alkyl, C Less than six} - alkylene _{-C 3 to 8} - _{cycloalkyl, C Less than six} - alkylene _{-C 3 to 8} - hetero Independently selected from the group consisting of cycloalkyl, 5 or 6 membered heteroaryl and phenyl, wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are unsubstituted or halogen; CN, OH, _oxo, CO 2 _{H, C 1~3} - alkyl, halo _{-C 1 to 3} - alkyl, _{O-C 1 to 3} - alkyl, O- halo _{-C 1 to 3} - alkyl, SO ₃ H and Substituted with 1 to 6 substituents independently selected from the group consisting of SO ₂ -C _1-3 -alkyl,
R ⁸ is independently selected from the group consisting of hydrogen, C _1-6 -alkyl, halo-C _1-6 -alkyl and C _3-6 -cycloalkyl,
Alternatively, R ⁷ and R ⁸ together with the nitrogen to which they are attached contain a carbon atom and optionally contain 1 or 2 heteroatoms selected from O, S or N A 3- to 8-membered ring may be completed, wherein said ring is unsubstituted or grouped of fluoro, OH, oxo, C _1-4 -alkyl and halo-C _1-4 -alkyl Substituted with 1 to 4 substituents independently selected from
A is 6-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic containing 1-5 heteroatoms independently selected from the group consisting of N, O and S Or bicyclic heteroaryl, where aryl and heteroaryl are unsubstituted or OH, halogen, CN, O—C _1-6 -alkyl, O-halo-C _1-6 -alkyl 1 or 2 groups independently selected from the group consisting of C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-6 -cycloalkyl and halo-C _3-6 -cycloalkyl Has been replaced,
Q is a C _5-8 -cycloalkyl ring and the —O—CH ₂ —Z-substituent is not directly adjacent to substituent A,
Z is

Selected from
Where
L is selected from the group consisting of a bond, C _1-3 -alkylene and C _1-3 -alkylene-O—
Y is selected from the group consisting of phenyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C _4-8 -cycloalkyl and C _4-8 -heterocycloalkyl, wherein phenyl, pyridyl, pyridyl -N- oxide, pyrimidyl, pyridinonyl, _{pyrimidinonyl, C 4 to 8} - cycloalkyl and _{C 4 to 8} - heterocycloalkyl is substituted with ^{R 2} and ^{R 3,} fluoro, chloro, _CN, NH 2, NH (C _1-3 -alkyl), N (C _1-3 -alkyl) ₂ , C _1-3 -alkyl, fluoro-C _1-3 -alkyl, OH, C _1-3 -alkoxy, fluoro-C _{1- 3} - _{alkoxy, C 3 to 6} - cycloalkyl and fluoro _{-C 3 to 6} - with a group selected from cycloalkyl Or twice, it is optionally substituted,
R ¹ is selected from the group consisting of C _1-4 -alkyl and C _3-6 -cycloalkyl, wherein C _1-4 -alkyl is unsubstituted or fluoro, hydroxy, C _{1- 3} - alkoxy and fluoro -C _{1 to 3 -} are substituted with one to three substituents independently selected from the group consisting of alkoxy, and C _{3 to 6 -} or cycloalkyl is unsubstituted, or 1 to 3 substitutions independently selected from the group consisting of fluoro, hydroxy, C _1-3 -alkyl, fluoro-C _1-3 -alkyl, C _1-3 -alkoxy and fluoro-C _1-3 -alkoxy Substituted with a group,
R ² and R ³ are hydrogen, halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, cyclopropyl and fluoro-cyclopropyl Independently selected from the group consisting of
R ⁴ is halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, C _3-6 -cycloalkyl and fluoro-C _{3. 6 -} is independently selected from the group consisting of cycloalkyl,
R ⁵ is selected from the group consisting of hydrogen, fluoro, CH ₃ , CHF ₂ and CF ₃ ;
n is selected from 0, 1, 2, 3 and 4;
x is selected from 0, 1 and 2.]
(Item 3)
R _{is, CO 2 H, SO 3 H} , CONR 7 R 8, tetrazolyl, 1,2,4-oxadiazol -5 (4H) - is selected from the group consisting of on-3-yl and _SO 2 NHCOR ^7,
R ⁷ is selected from the group consisting of hydrogen, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _1-6 -alkylene-R ⁹ and SO ₂ -C _1-3 -alkyl;
R ⁸ is selected from the group consisting of hydrogen, C _1-6 -alkyl and halo-C _1-6 -alkyl;
R ⁹ is, COOH, it is selected from the group consisting of OH and SO ₃ H, A compound according to claim 1 or 2.
(Item 4)
A is phenyl, pyridyl, pyrimidyl, pyrazolyl, indolyl, thienyl, benzothienyl, indazolyl, benzisoxazolyl, benzisothiazolyl, triazolopyridinyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, Selected from the group consisting of oxadiazolyl, oxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, each unsubstituted or OH, halogen, CN, O—C _1-6 -alkyl, O-halo-C _1-6 1 or 2 independently selected from the group consisting of -alkyl, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-6 -cycloalkyl and halo-C _3-6 -cycloalkyl Any one of claims 1 to 3 substituted with a group The compounds described.
(Item 5)
A is selected from the group consisting of phenyl, pyridyl, indolyl, indazolyl, benzisothiazolyl, triazolopyridinyl, benzothiazolyl, thiazolyl, oxazolyl, quinolyl, each unsubstituted or OH, halogen, CN , _{O-C 1 to 6} - alkyl, O- halo _{-C 1 to 6} - _{alkyl, C 1 to 6} - alkyl, halo _{-C 1 to 6} - _{alkyl, C 3 to 6} - cycloalkyl and halo _{-C. 3 to} 5. A compound according to claim 4, substituted with 1 or 2 groups independently selected from the group consisting of ₆ -cycloalkyl.
(Item 6)
R-A is

6. A compound according to any one of claims 1 to 5 selected from
(Item 7)
Z is

Selected from
Where
L is selected from the group consisting of a bond, C _1-3 -alkylene and C _1-3 -alkylene-O—
X is selected from the group consisting of CH, CF, N and NO;
R ¹ is selected from the group consisting of C _1-4 -alkyl and C _3-6 -cycloalkyl, wherein C _1-4 -alkyl is unsubstituted or fluoro, hydroxy, C _{1- 3} - alkoxy and fluoro -C _{1 to 3 -} are substituted with one to three substituents independently selected from the group consisting of alkoxy, C _{3 to 6 -} cycloalkyl, unsubstituted or 1 to 3 substitutions independently selected from the group consisting of fluoro, hydroxy, C _1-3 -alkyl, fluoro-C _1-3 -alkyl, C _1-3 -alkoxy and fluoro-C _1-3 -alkoxy Substituted with a group,
R ² and R ³ are hydrogen, halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, cyclopropyl and fluoro-cyclopropyl Independently selected from the group consisting of
R ⁵ is hydrogen, _fluoro, CH 3, CHF is selected from ₂ the group consisting of CF _3, A compound according to any one of claims 1 6.
(Item 8)
Z is

Selected from
Where
X is selected from the group consisting of CH, CF, N and NO;
R ¹ is selected from the group consisting of methyl, CF ₃ , CHF ₂ , isopropyl and cyclopropyl, where isopropyl and cyclopropyl are unsubstituted or are 1 or 2 fluoro or 1 hydroxy Is replaced with
R ² is selected from the group consisting of fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ ;
R ³ is selected from the group consisting of hydrogen, fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ ;
R ⁵ is hydrogen, _fluoro, CH 3, CHF is selected from ₂ the group consisting of CF _3, A compound according to any one of claims 1 to 7.
(Item 9)

But,

It is selected from, respectively, in R ^4, which are optionally substituted, compound according to any one of claims 1 to 8.
(Item 10)
10. A compound according to any one of claims 1 to 9 according to formula (2)

[Where:
A is phenyl, pyridyl, pyrimidyl, pyrazolyl, indolyl, thienyl, benzothienyl, indazolyl, benzisoxazolyl, benzisothiazolyl, triazolopyridinyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, Selected from the group consisting of oxadiazolyl, oxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, each unsubstituted or OH, halogen, CN, O—C _1-6 -alkyl, O-halo-C _1-6 1 or 2 independently selected from the group consisting of -alkyl, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-6 -cycloalkyl and halo-C _3-6 -cycloalkyl Substituted with a group,
R is selected from the group consisting of CO ₂ H, SO ₃ H, CONR ⁷ R ⁸ , tetrazolyl, 1,2,4-oxadiazol-5 (4H) -on -3-yl and SO ₂ NHCOR ⁷ ; here,
R ⁷ is selected from the group consisting of H, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _1-6 -alkylene-R ⁹ and SO ₂ -C _1-6 -alkyl;
R ⁸ is selected from the group consisting of H, C _1-6 -alkyl, halo-C _1-6 -alkyl, R ⁹ is selected from the group consisting of COOH, OH and SO ₃ H;
Z is

Selected from
X is selected from the group consisting of CH, N and NO;
R ¹ is selected from the group consisting of methyl, isopropyl and cyclopropyl, wherein isopropyl and cyclopropyl are unsubstituted or substituted with 1 or 2 fluoro or 1 hydroxy;
R ² is selected from the group consisting of fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ ;
R ³ is selected from the group consisting of hydrogen, fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ ].
(Item 11)

Or a compound selected from the group consisting of: enantiomers, diastereomers, tautomers, solvates, prodrugs or pharmaceutically acceptable salts thereof.
(Item 12)
12. A compound according to any one of claims 1 to 11 as a medicament.
(Item 13)
12. A compound according to any one of claims 1 to 11 for use in the prevention and / or treatment of a disease mediated by FXR.
(Item 14)
The disease is
Chronic intrahepatic or some forms of extrahepatic cholestasis,
Liver fibrosis,
Obstructive or chronic inflammatory disorders of the liver,
Cirrhosis,
Cholestatic or fibrotic effects associated with fatty liver and related syndromes, alcohol-induced cirrhosis or with virus-mediated forms of hepatitis,
Liver failure or ischemia after extensive hepatectomy,
Chemotherapy-related steatohepatitis (CASH);
Acute liver failure, and
Inflammatory bowel disease
14. A compound for use according to claim 13, selected from:
(Item 15)
The disease is
Lipid and lipoprotein disorders,
Clinical complications of type I and type II diabetes, including type II diabetes and other observed effects of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and clinically distinct long-term diabetes,
Conditions and diseases resulting from chronic fat and fibrotic degeneration of organs by forced accumulation of lipids, specifically triglycerides and subsequent activation of the pro-fibrotic pathway, such as nonalcoholic fatty liver disease (NAFLD), Or non-alcoholic steatohepatitis (NASH),
Obesity or metabolic syndrome (dyslipidemia, diabetes or a complex state of abnormally high body mass index), and
Acute myocardial infarction, acute stroke or thrombosis that occurs as an endpoint of chronic obstructive atherosclerosis
14. A compound for use according to claim 13, selected from:
(Item 16)
Said disease is non-malignant hyperproliferative disorder and malignant hyperproliferative disorder, specifically hepatocellular carcinoma, colon adenoma and polyposis, colon adenocarcinoma, breast cancer, pancreatic adenocarcinoma, Barrett's esophagus, or gastrointestinal tract and liver 14. A compound for use according to claim 13 selected from other forms of neoplastic diseases.

Claims (16)

A compound according to the following formula (1), its enantiomer, diastereomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt

[Where:
R is hydrogen, halogen, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, halo-C _1-6 -alkyl, C _0-6 -alkylene-R ⁷ , C _{0- 6} -alkylene-O—R ⁷ , C _0-6 -alkylene-CN, C _0-6 -alkylene-NR ⁷ R ⁸ , O—C _3-10 -cycloalkyl, O—C _1-6 -alkylene-O -R ^7, _O-C 3~10 - _{heterocycloalkyl, C Less than six} - alkylene _-CO 2 ^R _{7, C 0~6} - alkylene _{^{-C (O) R 7, C}} 0~6 - alkylene -C ( _{^{O) NR 7 R 8, C}} 0~6 - alkylene ^{_{-C (O) NR 7 SO 2}} R 7, C 0~6 - alkylene ^{-N (R 7) C (O} ) R 7, C 0~6 - alkylene _{-SO x} -R ^7, _C 0~6 - alkylene _-SO 3 H, _{C 0 6} - alkylene ^{_{-SO 2 -NR 7 R 8, C}} 0~6 - alkylene ^{_{-SO 2 -NR 8 COR 7, C}} 0~6 - alkylene _{^{-N (R 7) SO 2 -R}} 8, and _{C 0 to 6} - alkylene _-SO 2 _{-C 3 to 10} - is selected from the group consisting of heterocycloalkyl,
Where alkylene, cycloalkyl, heterocycloalkyl and 5- or 6-membered heteroaryl are unsubstituted or halogen, CN, C _1-3 -alkyl, halo-C _1-3 -alkyl, OH, _{oxo, CO 2 H, SO 3 H} , O-C 1~3 - is substituted by one to four substituents selected from the group consisting of alkyl independently - alkyl and O- halo _{-C 1 to 3} ,
R ⁷ is hydrogen, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _0-6 -alkylene-C _3-8 -cycloalkyl, C _0-6 -alkylene-C _{3-8 -hetero.} Independently selected from the group consisting of cycloalkyl, 5 or 6 membered heteroaryl and phenyl, wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are unsubstituted or halogen; CN, OH, _oxo, CO 2 _{H, C 1~3} - alkyl, halo _{-C 1 to 3} - alkyl, _{O-C 1 to 3} - alkyl, O- halo _{-C 1 to 3} - alkyl, SO ₃ H and Substituted with 1 to 6 substituents independently selected from the group consisting of SO ₂ -C _1-3 -alkyl,
R ⁸ is independently selected from the group consisting of hydrogen, C _1-6 -alkyl, halo-C _1-6 -alkyl and C _3-6 -cycloalkyl,
Alternatively, R ⁷ and R ⁸ together with the nitrogen to which they are attached contain a carbon atom and optionally contain 1 or 2 heteroatoms selected from O, S or N A 3- to 8-membered ring may be completed, wherein said ring is unsubstituted or grouped of fluoro, OH, oxo, C _1-4 -alkyl and halo-C _1-4 -alkyl Substituted with 1 to 4 substituents independently selected from
A is 6-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic containing 1-5 heteroatoms independently selected from the group consisting of N, O and S Or bicyclic heteroaryl, where aryl and heteroaryl are unsubstituted or OH, halogen, CN, O—C _1-6 -alkyl, O-halo-C _1-6 -alkyl Independently selected from the group consisting of C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-6 -cycloalkyl, C _5-6 -heterocycloalkyl and halo-C _3-6 -cycloalkyl Substituted with 1 or 2 groups
Q is a C _3-10 -cycloalkyl ring, or a C _{5-10 -bridged} cycloalkyl ring, and the —O—CH ₂ —Z-substituent is not directly adjacent to substituent A, and Q is When it is a bicyclic or polycyclic ring system, the carbon atom may be optionally replaced with oxygen, SO _x or NR ⁷ ,
Z is

In the formula selected from
L is selected from the group consisting of a bond, C _1-3 -alkylene and C _1-3 -alkylene-O—
Y is selected from the group consisting of phenyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C _4-8 -cycloalkyl and C _4-8 -heterocycloalkyl, wherein phenyl, pyridyl, pyridyl -N- oxide, pyrimidyl, pyridinonyl, _{pyrimidinonyl, C 4 to 8} - cycloalkyl and _{C 4 to 8} - heterocycloalkyl is substituted with ^{R 2} and ^{R 3,} fluoro, chloro, _CN, NH 2, NH (C _1-3 -alkyl), N (C _1-3 -alkyl) ₂ , C _1-3 -alkyl, fluoro-C _1-3 -alkyl, OH, C _1-3 -alkoxy, fluoro-C _{1- 3} - _{alkoxy, C 3 to 6} - cycloalkyl and fluoro _{-C 3 to 6} - with a group selected from cycloalkyl Or twice, it is optionally substituted,
R ¹ is selected from the group consisting of C _1-4 -alkyl and C _3-6 -cycloalkyl, wherein C _1-4 -alkyl is unsubstituted or fluoro, hydroxy, C _{1- 3} - alkoxy and fluoro -C _{1 to 3 -} are substituted with one to three substituents independently selected from the group consisting of alkoxy, and C _{3 to 6 -} or cycloalkyl is unsubstituted, or 1 to 3 substitutions independently selected from the group consisting of fluoro, hydroxy, C _1-3 -alkyl, fluoro-C _1-3 -alkyl, C _1-3 -alkoxy and fluoro-C _1-3 -alkoxy Substituted with a group,
R ² and R ³ are hydrogen, halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, cyclopropyl and fluoro-cyclopropyl Independently selected from the group consisting of
R ⁴ is halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, C _3-6 -cycloalkyl, C _1-3 Independently selected from the group consisting of -alkylene-O-C _1-3 -alkyl and fluoro-C _3-6 -cycloalkyl;
R ⁵ is selected from the group consisting of hydrogen, fluoro, CH ₃ , CHF ₂ and CF ₃ ;
n is selected from 0, 1, 2, 3 and 4;
x is independently selected from 0, 1 and 2.] A compound according to the following formula (1), its enantiomer, diastereomer, tautomer, solvate, prodrug or pharmaceutically acceptable salt

[Where:
R is hydrogen, _{halogen, C 1 to 6} - _{alkyl, C 2 to 6} - _{alkenyl, C 2 to 6} - alkynyl, halo _{-C 1 to 6} - _{alkyl, C Less than six} - alkylene ^-O-R 7, C _0-6 - alkylene _{-CN, C 0-6} - alkylene _{^{-NR 7 R 8, O-C}} 3~10 - cycloalkyl, _{O-C 1 to 6} - alkylene _{^{-O-R 7, O-C}} 3~10 - _{heterocycloalkyl, C Less than six} - alkylene _-CO 2 ^R _{7, C 0~6} - alkylene _{^{-C (O) R 7, C}} 0~6 - alkylene ^{-C (O) NR 7 R 8} , C 0~ ₆ - alkylene ^{_{-C (O) NR 7 SO 2}} R 7, C 0~6 - alkylene ^{-N (R 7) C (O} ) R 7, C 0~6 - alkylene _-SO x ^-R _{7, C 0~ 6} - alkylene _-SO 3 _{H, C 0~6} - alkylene _-SO 2 -N ⁷ R ^8, _{C 0~6} - alkylene ^{_{-SO 2 -NR 8 COR 7, C}} 0~6 - alkylene _{^{-N (R 7) SO 2 -R}} 8, and _{C Less than six} - alkylene _-SO 2 -C ₃ Selected from the group consisting of ₁₀ -heterocycloalkyl,
Where alkylene, cycloalkyl, heterocycloalkyl and 5- or 6-membered heteroaryl are unsubstituted or halogen, CN, C _1-3 -alkyl, halo-C _1-3 -alkyl, OH, _{oxo, CO 2 H, SO 3 H} , O-C 1~3 - is substituted by one to four substituents selected from the group consisting of alkyl independently - alkyl and O- halo _{-C 1 to 3} ,
R ⁷ is hydrogen, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _0-6 -alkylene-C _3-8 -cycloalkyl, C _0-6 -alkylene-C _{3-8 -hetero.} Independently selected from the group consisting of cycloalkyl, 5 or 6 membered heteroaryl and phenyl, wherein alkyl, alkylene, cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are unsubstituted or halogen; CN, OH, _oxo, CO 2 _{H, C 1~3} - alkyl, halo _{-C 1 to 3} - alkyl, _{O-C 1 to 3} - alkyl, O- halo _{-C 1 to 3} - alkyl, SO ₃ H and Substituted with 1 to 6 substituents independently selected from the group consisting of SO ₂ -C _1-3 -alkyl,
R ⁸ is independently selected from the group consisting of hydrogen, C _1-6 -alkyl, halo-C _1-6 -alkyl and C _3-6 -cycloalkyl,
Alternatively, R ⁷ and R ⁸ together with the nitrogen to which they are attached contain a carbon atom and optionally contain 1 or 2 heteroatoms selected from O, S or N A 3- to 8-membered ring may be completed, wherein said ring is unsubstituted or grouped of fluoro, OH, oxo, C _1-4 -alkyl and halo-C _1-4 -alkyl Substituted with 1 to 4 substituents independently selected from
A is 6-10 membered monocyclic or bicyclic aryl, or 5-10 membered monocyclic containing 1-5 heteroatoms independently selected from the group consisting of N, O and S Or bicyclic heteroaryl, where aryl and heteroaryl are unsubstituted or OH, halogen, CN, O—C _1-6 -alkyl, O-halo-C _1-6 -alkyl 1 or 2 groups independently selected from the group consisting of C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-6 -cycloalkyl and halo-C _3-6 -cycloalkyl Has been replaced,
Q is a C _5-8 -cycloalkyl ring and the —O—CH ₂ —Z-substituent is not directly adjacent to substituent A,
Z is

In the formula selected from
L is selected from the group consisting of a bond, C _1-3 -alkylene and C _1-3 -alkylene-O—
Y is selected from the group consisting of phenyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C _4-8 -cycloalkyl and C _4-8 -heterocycloalkyl, wherein phenyl, pyridyl, pyridyl -N- oxide, pyrimidyl, pyridinonyl, _{pyrimidinonyl, C 4 to 8} - cycloalkyl and _{C 4 to 8} - heterocycloalkyl is substituted with ^{R 2} and ^{R 3,} fluoro, chloro, _CN, NH 2, NH (C _1-3 -alkyl), N (C _1-3 -alkyl) ₂ , C _1-3 -alkyl, fluoro-C _1-3 -alkyl, OH, C _1-3 -alkoxy, fluoro-C _{1- 3} - _{alkoxy, C 3 to 6} - cycloalkyl and fluoro _{-C 3 to 6} - with a group selected from cycloalkyl Or twice, it is optionally substituted,
R ¹ is selected from the group consisting of C _1-4 -alkyl and C _3-6 -cycloalkyl, wherein C _1-4 -alkyl is unsubstituted or fluoro, hydroxy, C _{1- 3} - alkoxy and fluoro -C _{1 to 3 -} are substituted with one to three substituents independently selected from the group consisting of alkoxy, and C _{3 to 6 -} or cycloalkyl is unsubstituted, or 1 to 3 substitutions independently selected from the group consisting of fluoro, hydroxy, C _1-3 -alkyl, fluoro-C _1-3 -alkyl, C _1-3 -alkoxy and fluoro-C _1-3 -alkoxy Substituted with a group,
R ² and R ³ are hydrogen, halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, cyclopropyl and fluoro-cyclopropyl Independently selected from the group consisting of
R ⁴ is halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, C _3-6 -cycloalkyl and fluoro-C _{3. 6 -} is independently selected from the group consisting of cycloalkyl,
R ⁵ is selected from the group consisting of hydrogen, fluoro, CH ₃ , CHF ₂ and CF ₃ ;
n is selected from 0, 1, 2, 3 and 4;
x is selected from 0, 1 and 2.] R _{is, CO 2 H, SO 3 H} , CONR 7 R 8, tetrazolyl, 1,2,4-oxadiazol -5 (4H) - is selected from the group consisting of on-3-yl and _SO 2 NHCOR ^7,
R ⁷ is selected from the group consisting of hydrogen, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _1-6 -alkylene-R ⁹ and SO ₂ -C _1-3 -alkyl;
R ⁸ is selected from the group consisting of hydrogen, C _1-6 -alkyl and halo-C _1-6 -alkyl;
R ⁹ is, COOH, it is selected from the group consisting of OH and SO ₃ H, A compound according to claim 1 or 2. A is phenyl, pyridyl, pyrimidyl, pyrazolyl, indolyl, thienyl, benzothienyl, indazolyl, benzisoxazolyl, benzisothiazolyl, triazolopyridinyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, Selected from the group consisting of oxadiazolyl, oxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, each unsubstituted or OH, halogen, CN, O—C _1-6 -alkyl, O-halo-C _1-6 1 or 2 independently selected from the group consisting of -alkyl, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-6 -cycloalkyl and halo-C _3-6 -cycloalkyl Any one of claims 1 to 3 substituted with a group The compounds described. A is selected from the group consisting of phenyl, pyridyl, indolyl, indazolyl, benzisothiazolyl, triazolopyridinyl, benzothiazolyl, thiazolyl, oxazolyl, quinolyl, each unsubstituted or OH, halogen, CN , _{O-C 1 to 6} - alkyl, O- halo _{-C 1 to 6} - _{alkyl, C 1 to 6} - alkyl, halo _{-C 1 to 6} - _{alkyl, C 3 to 6} - cycloalkyl and halo _{-C. 3 to} 5. A compound according to claim 4, substituted with 1 or 2 groups independently selected from the group consisting of ₆ -cycloalkyl. R-A is

6. A compound according to any one of claims 1 to 5 selected from Z is

Selected from
Where
L is selected from the group consisting of a bond, C _1-3 -alkylene and C _1-3 -alkylene-O—
X is selected from the group consisting of CH, CF, N and NO;
R ¹ is selected from the group consisting of C _1-4 -alkyl and C _3-6 -cycloalkyl, wherein C _1-4 -alkyl is unsubstituted or fluoro, hydroxy, C _{1- 3} - alkoxy and fluoro -C _{1 to 3 -} are substituted with one to three substituents independently selected from the group consisting of alkoxy, C _{3 to 6 -} cycloalkyl, unsubstituted or 1 to 3 substitutions independently selected from the group consisting of fluoro, hydroxy, C _1-3 -alkyl, fluoro-C _1-3 -alkyl, C _1-3 -alkoxy and fluoro-C _1-3 -alkoxy Substituted with a group,
R ² and R ³ are hydrogen, halogen, C _1-3 -alkyl, halo-C _1-3 -alkyl, C _1-3 -alkoxy, halo-C _1-3 -alkoxy, cyclopropyl and fluoro-cyclopropyl Independently selected from the group consisting of
R ⁵ is hydrogen, _fluoro, CH 3, CHF is selected from ₂ the group consisting of CF _3, A compound according to any one of claims 1 6. Z is

Selected from
Where
X is selected from the group consisting of CH, CF, N and NO;
R ¹ is selected from the group consisting of methyl, CF ₃ , CHF ₂ , isopropyl and cyclopropyl, where isopropyl and cyclopropyl are unsubstituted or are 1 or 2 fluoro or 1 hydroxy Is replaced with
R ² is selected from the group consisting of fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ ;
R ³ is selected from the group consisting of hydrogen, fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ ;
R ⁵ is hydrogen, _fluoro, CH 3, CHF is selected from ₂ the group consisting of CF _3, A compound according to any one of claims 1 to 7.

But,

It is selected from, respectively, in R ^4, which are optionally substituted, compound according to any one of claims 1 to 8. 10. A compound according to any one of claims 1 to 9 according to formula (2)

[Where:
A is phenyl, pyridyl, pyrimidyl, pyrazolyl, indolyl, thienyl, benzothienyl, indazolyl, benzisoxazolyl, benzisothiazolyl, triazolopyridinyl, benzofuranyl, benzotriazolyl, furanyl, benzothiazolyl, thiazolyl, Selected from the group consisting of oxadiazolyl, oxazolyl, naphthyl, quinolyl, isoquinolyl, benzimidazolyl, each unsubstituted or OH, halogen, CN, O—C _1-6 -alkyl, O-halo-C _1-6 1 or 2 independently selected from the group consisting of -alkyl, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _3-6 -cycloalkyl and halo-C _3-6 -cycloalkyl Substituted with a group,
R is selected from the group consisting of CO ₂ H, SO ₃ H, CONR ⁷ R ⁸ , tetrazolyl, 1,2,4-oxadiazol-5 (4H) -on-3-yl and SO ₂ NHCOR ⁷ ; here,
R ⁷ is selected from the group consisting of H, C _1-6 -alkyl, halo-C _1-6 -alkyl, C _1-6 -alkylene-R ⁹ and SO ₂ -C _1-6 -alkyl;
R ⁸ is selected from the group consisting of H, C _1-6 -alkyl, halo-C _1-6 -alkyl,
R ⁹ is selected from the group consisting of COOH, OH and SO ₃ H;
Z is

Selected from
X is selected from the group consisting of CH, N and NO;
R ¹ is selected from the group consisting of methyl, isopropyl and cyclopropyl, wherein isopropyl and cyclopropyl are unsubstituted or substituted with 1 or 2 fluoro or 1 hydroxy;
R ² is selected from the group consisting of fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ ;
R ³ is selected from the group consisting of hydrogen, fluoro, chloro, CH ₃ , CHF ₂ , CF ₃ , OCHF ₂ and OCF ₃ ].

Or a compound selected from the group consisting of: enantiomers, diastereomers, tautomers, solvates, prodrugs or pharmaceutically acceptable salts thereof.   12. A compound according to any one of claims 1 to 11 as a medicament.   12. A compound according to any one of claims 1 to 11 for use in the prevention and / or treatment of a disease mediated by FXR. The disease is
Chronic intrahepatic or some forms of extrahepatic cholestasis,
Liver fibrosis,
Obstructive or chronic inflammatory disorders of the liver,
Cirrhosis,
Cholestatic or fibrotic effects associated with fatty liver and related syndromes, alcohol-induced cirrhosis or with virus-mediated forms of hepatitis,
Liver failure or ischemia after extensive hepatectomy,
Chemotherapy-related steatohepatitis (CASH);
14. A compound for use according to claim 13, selected from acute liver failure, as well as inflammatory bowel disease. The disease is
Lipid and lipoprotein disorders,
Clinical complications of type I and type II diabetes, including type II diabetes and other observed effects of diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and clinically distinct long-term diabetes,
Conditions and diseases resulting from chronic fat and fibrotic degeneration of organs by forced accumulation of lipids, specifically triglycerides and subsequent activation of the pro-fibrotic pathway, such as nonalcoholic fatty liver disease (NAFLD), Or non-alcoholic steatohepatitis (NASH),
Select from acute myocardial infarction, acute stroke, or thrombosis that occurs as an endpoint of obesity or metabolic syndrome (dyslipidemia, diabetes or complex body mass index condition), and chronic obstructive atherosclerosis 14. A compound for use according to claim 13, wherein:   The disease is a non-malignant hyperproliferative disorder and a malignant hyperproliferative disorder, specifically hepatocellular carcinoma, colon adenoma and polyposis, colon adenocarcinoma, breast cancer, pancreatic adenocarcinoma, Barrett's esophagus, or gastrointestinal tract and liver 14. A compound for use according to claim 13 selected from other forms of neoplastic diseases.